2025+SNMMI／EANM／ASNC／ACNM程序标准／实践指南：18F-氟吡啶唑+PET心肌灌注成像及血流定量

SNMMI/EANM/ASNC/ACNM procedure standard/practice grudeline for 18F-Flurpiridaz PET myocardial perfusion imaging and blood flow quantitation

René R. Sevag Packard, MD, PhD 1,, Jamshid Maddahi, MD 2, Matthieu Pelletier-Galarneau, MD 3,Mouaz H. Al-Mallah, MD, MSc 4, Marta Coelho 5, Sharmila Dorbala, MD, MPH 6, James Galt, PhD 7,Mark Hyun, CNMT, NCT, RS, RT(N,R,CT) 8, Nandakumar Menon, MD 9 Edward J. Miller, MD, PhD 10, Mrinal Shetty, MD 11, Antti Saraste, MD, PhD 12

$^{1}$ Division of Cardiology, Department of Medicine; Department of Physiology; California NanoSystems Institute; and David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

$^{2}$ Division of Cardiology, Department of Medicine; Department of Molecular and Medical Pharmacology; and David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

$^{3}$ Department of Medical Imaging, Montreal Institute, University of Montreal, Montreal, Quebec, Canada

4Houston Methodist DeBakey Heart& Vascular Center, Houston, TX, USA

$^{5}$ Department of Nuclear Medicine, West German Cancer Center, University Hospital Essen and University of Duisburg-Essen, Essen,Germany

${}^{6}$ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Cardiovascular Imaging Program, Departments of Medicine and Radiology and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

7Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta,GA,USA

${}^{8}$ Department of Imaging and Cedars-Sinai Medical Center, Los Angeles, CA, USA

${}^{9}$ Department of Radiology, University of Wisconsin, Madison, WI, USA

${}^{10}$ Section of Cardiovascular Medicine, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

$^{11}$ Division of Cardiovascular Medicine, Department of Medicine, University of Louisville School of Medicine, Louisville, Louisville

${}^{12}$ Heart Center and PET Centre, University of Turkuh and Turku University Hospital, Turku, Finland

${}^{*}$ Corresponding author.

E-mail address: rpackard@mednet.ucla.edu (René R. Sevag Packard).

Preamble

The Society of Nuclear Medicine and Molecular Imaging (SNMMI), founded in 1954 and headquartered in Reston, Virginia, USA, is a nonprofit scientific and professional organization that promotes the science, technology, and practical application of nuclear medicine and molecular imaging. SNMMI strives to be a leader in unifying, advancing,and optimizing molecular imaging with the ultimate goal of improving human health.With 13,000 members worldwide, SNMMI represents nuclear and molecular imaging professionals, all of whom are committed to the advancement of the field. The European Association of Nuclear Medicine (EANM) is a professional, nonprofit medical association that facilitates communication worldwide between individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985.The American College of Nuclear Medicine (ACNM) is a professional organization providing education, training, and advocacy for the most sought-after and trusted experts in nuclear medicine who deliver state-of-the-art and innovative care and service to patients and referring physicians. The ACNM's mission is to foster the highest standards in nuclear medicine consultation and service to referring physicians,hospitals, and the public, and to advance the science of nuclear medicine through a

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program of continuing professional development emphasizing high standards of nuclear medicine practice. The American Society of Nuclear Cardiology(ASNC) is the international home for nuclear cardiology and the largest professional society devoted exclusively to the field. ASNC membership includes more than 5700 nuclear cardiology professionals from around the world. Founded in 1993, ASNC's mission is to improve cardiovascular outcomes through image-guided patient management. ASNC's official publication is the Journal of Nuclear Cardiology.

The SNMMI/EANM/ACNM will periodically define new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and to improve the quality of service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated.

Each standard/guideline, representing a policy statement by the SNMMI/EANM/ACNM,has undergone a thorough consensus process in which it has been subjected to extensive review. The SNMMI, EANM, and ACNM recognize that the safe and effective use of diagnostic nuclear medicine imaging and therapy requires specific training,skills, and techniques, as described in each document. This document was jointly developed with ASNC. ASNC endorses this guideline, and it will be published alongside the Journal of Nuclear Medicine in the Journal of Nuclear Cardiology.

The SNMMI, EANM, ASNC, and ACNM have written and approved these standards/guidelines to promote the use of high-quality nuclear medicine procedures. These standards/guidelines are intended to assist practitioners in providing appropriate care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI, EANM, ASNC, andACNM caution against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question.

The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals considering the unique circumstances of each case. Thus, there is no implication that an approach differing from the standards/guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such a course of action is indicated by the condition of the patient,limitations of available resources, or advances in knowledge or technology subsequent to publication of the standards/guidelines.

The practice of medicine involves not only the science but also the art of dealing with the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognized that adherence to these standards/guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these standards/guidelines is to assist practitioners in achieving this objective.

Quality control and improvement, safety, infection control, and patient education concerns

See the SNMMI Guideline for General Imaging. Policies and procedures related to quality,patient education, infection control, and safety should be developed and implemented in accordance with good quality control practices. Quality control should also be done regularly to assure consistent, accurate physician interpretation of results. Equipment performance monitoring should be in accordance with a recognized accreditation organization.

Documentation/reporting

See the SNMMI Guideline for General Imaging for documentation/reporting requirements.Radiation safety in imaging

See the SNMMI Guideline for General Imaging. It is the position of SNMMI that patient exposure to ionizing radiation should be at the minimum level consistent with

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obtaining a diagnostic examination. Reduction in patient radiation exposure may be accomplished by administering less radiopharmaceutical when the technique or equipment used for imaging can support such an action. Each patient procedure is unique and the methodology to achieve minimum exposure while maintaining diagnostic accuracy needs to be viewed in this light. Radiopharmaceutical activity ranges outlined in this document should be considered as a guide. Dose-reduction techniques should be utilized when appropriate. The same principles should be applied when CT is used in a hybrid imaging procedure. CT acquisition protocols should be optimized to provide the information needed while minimizing patient radiation exposure. Minimizing radiation dose is especially important in children.

The breastfeeding patient

See the Advisory Committee on the Medical Uses of Isotopes(ACMUI) guidelines.

Keywords: ${ }^{18}$ F-flurpiridaz, Positron emission tomography, Myocardial perfusion imaging,Myocardial blood flow，Practice guideline

ABBREVIATIONS

CAD Coronary artery disease

ECG Electrocardiogram

LV Left ventricular

LVEDV LV end-diastolic volume

LVEF LV ejection fraction

LVESV LV end-systolic volume

MBF Myocardial blood flow

MFR Myocardial flow reserve

MPI Myocardial perfusion imaging

PET Positron emission tomography

tomography

INTRODUCTION

Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide,resulting from progressive atherosclerotic nar-rowing of the epicardial coronary arteries and/or microvascular dysfunction and subsequent myocardial ischemia. Accurate diagnosis and risk stratification of CAD are essential for guiding therapeutic interventions and improving patient outcomes. Myocardial perfusion imaging (MPI)represents a cornerstone of the noninvasive assessment of myocardial ischemia [1,2].

Stress testing, achieved through either exer-cise or pharmacologic agents, is utilized to induce alterations in myocardial blood flow(MBF), thereby enabling the functional evalua-tion of myocardial perfusion under stress conditions [3,4]. Traditionally, MPI has been performed using single-photon emission

<EndOfPara>computed tomography(SPECT), which has served as the standard technique for the detection of myocardial ischemia. However,positron emission tomography(PET) offers several advantages over SPECT, including superior spatial resolution, improved diag-nostic accuracy, and the capacity for routine quantitative assessment of MBF in absolute terms[5-13].

${}^{18}$ F-flurpiridaz is a novel PET radiotracer that has demonstrated favorable imaging and physi-ological properties compared to conventional SPECT agents [14,15]. This agent binds with high affinity to mitochondrial complex I and exhibits a nearly linear relationship between MBF and tracer uptake [16]. Clinical studies have shown that ${}^{18}$ F-flurpiridaz PET imaging provides enhanced image quality, increased diagnostic accuracy, and greater sensitivity for the detection of significant coronary artery stenosis, particu-larly in patient populations where SPECT may be suboptimal, such as individuals with obesity or small left ventricles [15,17,18].

Multiple phase II and two phase III clinical trials have further established the utility of ${}^{18}$ F-flurpir-idaz as a valuable PET radiotracer for the nonin-vasive evaluation of CAD[15,19,20]. Like other PET MPI radiotracers, the ability to quantify MBF and myocardial flow reserve (MFR) provides incre-mental diagnostic value, especially in complex cases where precise assessment of CAD burden is critical [21]. Owing to its favorable molecular im-aging characteristics and extended half-life, ${}^{18}$ F-flurpiridaz is poised to become a valuable agent for cardiac stress PET imaging, offering clinicians a robust tool for the evaluation of CAD[22,23].

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DOCUMENT GOALS

This procedure standard/practice guideline is intended to assist nuclear cardiology practi-tioners in the appropriate use of ${ }^{18}$ F-flurpiridaz PET for MPI, including recommendations for pa-tient selection, imaging protocols, and interpre-tation of results. This document is based on current scientific evidence and expert consensus,and is designed to promote high-quality, safe,and effective nuclear medicine practice in the evaluation of CAD. It is intended for patients with suspected or known CAD to evaluate for myocardial ischemia and infarction. The recom-mendations in this document aim to enhance accuracy and optimize resource allocation. The goals of this document include:

- Enhance clinical decision-making

To provide clear, evidence-based guidelines that assist clinicians in determining when ${ }^{18}$ F-flurpir-idaz PET MPI is appropriate, ensuring its use is based on clinical need and patient benefit.

- Standardize clinical practice

To promote consistency in the application of ${ }^{18}$ F-flurpiridaz PET MPI across different health-care settings, thereby optimizing the quality of care and reducing variability in practice.

- Improve diagnostic accuracy

To outline specific indications and scenarios where ${ }^{18} ~F$ -flurpiridaz PET MPI has demonstrated superior diagnostic accuracy, aiding in the early detection and management of myocardial ischemia.

- Optimize resource utilization

To support the appropriate utilization of healthcare resources by identifying the patient populations most likely to benefit from ${ }^{18} ~F$ -flur-piridaz PET MPI.

- Enhance patient outcomes

To ensure that ${ }^{18} ~F$ -flurpiridaz PET MPI is used effectively to improve patient outcomes,including the timely diagnosis of CAD and the subsequent appropriate management of cardiac conditions.

- Facilitate education and training

To provide a comprehensive framework for healthcare providers to understand the in-dications, benefits, and limitations of ${ }^{18}$ F-

flurpiridaz PET MPI, enhancing knowledge and skills in its clinical application.

- Promote research and development

To identify gaps in current knowledge and encourage ongoing research in the field of MPI with ${ }^{18}$ F-flurpiridaz, fostering advancements in diagnostic techniques and patient care strategies.

- Ensure safety and efficacy

To establish guidelines that prioritize patient safety and the efficacy of ${ }^{18} ~F$ -flurpiridaz PET MPI,minimizing risks and ensuring the procedure is performed under optimal conditions.

BACKGROUND ON $^{18} ~F$ -FLURPIRIDAZ

${ }^{18}$ F-flurpiridaz (formerly BMS-747158-02 or 2-tert-butyl-4-chloro-5-[4-(2-(18F)fluoroethoxymethyl)-benzyloxy]-2H-pyridazin-3-1) is a fluorine-18-labeled myocardial perfusion tracer and a struc-tural analog of the insecticide pyridaben, binding with high affinity to nicotinamide adenine dinu-cleotide hydride (NADH):ubiquinone reductase(mitochondrial complex I) of the electron trans-port chain [24,25]. ${ }^{18}$ F-flurpiridaz inhibits mito-chondrial complex I by competing for binding with ubiquinone, without affecting car-diomyocyte viability [24].

Initial preclinical evaluation of ${ }^{18} ~F$ -flurpiridaz demonstrated highly favorable characteristics for MPI, including very high and sustained myocar-dial uptake proportional to MBF, high contrast between the myocardium and adjacent organs,and a high first-pass myocardial extraction frac-tion (94\%) even at high flow rates [24-29]. Activity ratios between myocardium and blood, liver, and lungs were 2 to 3 times higher with ${ }^{18} ~F$ -flurpiridaz than with ${ }^{13} ~N$ -ammonia during pharmacologic stress in pigs [27]. ${ }^{18} ~F$ -flurpiridaz PET images provided clear delineation of the myocardium and regional perfusion defects induced by constriction or ligation of epicardial coronary ar-teries [24-28]. The extent of perfusion defects correlated well with histologically determined myocardial infarct size after permanent $(r=.88$ ,mean difference $1.9 \%$ ) or transient $(r=.92$ , mean difference $2.2 \%$ ) coronary artery occlusion in rats[28]. In isolated rat hearts perfused with the Langendorff method, the tracer showed a high and flow-independent myocardial first-pass extraction fraction averaging $94 \%$ [26]. A valida-tion study in pigs demonstrated the feasibility and accuracy of MBF quantitation with ${ }^{18} ~F$ -flur -diridaz PET without corrections for metabolites or flow-dependent extraction [27]. Regional MBF assessed with ${ }^{18} ~F$ -flurpiridaz PET showed good

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correlation and modest underestimation compared to microsphere measurements $(r=.88$ ,slope 84, agreement $-.10~mL/ g/ min)$ over a wide flow range from. 1-3.0 mL/min/g, achieved using pharmacologic stress and epicardial coronary artery constriction[27]. Furthermore, a linear relationship between myocardial tracer uptake and blood flow was supported by standardized uptake value correlations with microsphere-measured MBF[29]. The absence of a"roll-off phenomenon"(defined as a nonlinear decrease in extraction fraction at higher flows) enables ac-curate measurement of MBF over the entire physiologic range of MBF values as well as greater accuracy for regional relative perfusion deficits.

In PET imaging, the spatial resolution is fundamentally limited by the positron range,which is presented here as the full width at tenth maximum (FWTM) of the positron annihilation point distribution in water [30]. Positron annhi-lation point spread functions are typically cusp-like, characterized by a sharp central peak and broad distribution tails, rather than a simple Gaussian profile. Consequently, the conventional full width at half maximum (FWHM) metric does not fully capture the extent of image blurring,especially for isotopes with higher positron en-ergies. Notably, the ${ }^{18} ~F$ positron range $(1.03 ~mm)$is significantly shorter than ${ }^{82} Rb(8.6 ~mm),{ }^{15} O$$(4.14 ~mm)$ , and ${ }^{13} ~N(2.53 ~mm)$ , yielding superior spatial resolution [22,30,31].

Together, the higher extraction fraction and shorter positron range result in improved image quality and higher defect contrast [26,32]. These promising experimental results supported the further development of ${ }^{18}$ F-flurpiridaz as a myocardial perfusion tracer [33].

Clinical studies have evaluated 18F-flurpiridaz for safety, imaging characteristics, and applica-tion in the evaluation of CAD in more than 2000 subjects undergoing pharmacologic or exercise stress [15,19,20,34-36]. 18F-flurpiridaz was well tolerated, with no clinically relevant safety con-cerns raised. The mean effective radiation dose of 18F-flurpiridaz is approximately 019 mSv/MBq,enabling rest-stress MPI with lower radiation exposure compared to 99mTc-labeled SPECT MPI[34,35], but higher than with other PET MPI probes. 18F-flurpiridaz PET demonstrated superior image quality and greater interpretive confidence compared to SPECT for the detection of CAD[15,19,20]. In two prospective multicenter phase III trials, 18F-flurpiridaz PET demonstrated supe-rior sensitivity (80.3%) and overall diagnostic performance (area under the receiver operating characteristic curve .80) for detection of obstruc-tive CAD (≥50% stenosis) compared to $99 ~mTc-$labeled SPECT MPI, with superior performance in

patient subsets of women, obese individuals(body mass index $\geq 30kg/m^{2}$ ), and those with small left ventricular cavities[15,17,18,20].

Experimental validation and clinical experience indicate the feasibility of MBF quantitation with ${ }^{18}$ F-flurpiridaz [17,21,27,28,37-39]. Higher image reso-lution and myocardial extraction fraction, absence of roll-off phenomenon, the potential for single-dose delivery to sites without an onsite cyclotron,and the ability to use in conjunction with treadmill exercise [40] distinguish ${ }^{18}$ F-flurpiridaz from currently available PET perfusion tracers.

CLINICAL INDICATIONS, CONTRAINDICATIONS,AND CONSIDERATIONS

Clinical indications

● Evaluation of symptomatic patients

Similar to other PET MPI radiopharmaceuticals[12], ${}^{18}$ F-flurpiridaz PET MPIindications [13]include:

o Assess chest pain or equivalent symptoms in individuals with intermediate to high pretest probability of CAD.

o Detect flow-limiting obstructive CAD.

o Risk stratify patients with CAD.

o Evaluate suspected coronary microvascular disease.

● Asymptomatic high-risk populations

o Selective use in asymptomatic individuals with high atherosclerotic cardiovascular disease (ASCDV) risk (≥20% 10-year risk)when noninvasive testing is warranted.

● Quantitative myocardial blood flow assessment

${}^{18}$ F-Flurpiridaz PET is indicated for absolute quantitation of hyperemic MBF and MFRto:

o Identify multivessel CAD patterns.

o Assess the physiological significance of an-giographical indeterminate epicardial CAD.

o Diagnose coronary microvascular disease in patients without obstructive epicardial disease.

o Quantitation of MBF also enables detection of suboptimal response to pharmacologic stress leading to no or minimal increase of stress MBF compared to rest MBF.

Absolute contraindications

● Pregnancy is an absolute contraindication.

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● Additional contraindications are linked to vasodilator stress (i.e. not radiopharmaceutical administration), as per routine clinical prac-tice. These include acute myocardial infarction(within the previous 2-4 days); unstable angina or acute coronary syndrome; second- or third-degree atrioventricular (AV) block or sinus node dysfunction (such as sick sinus syndrome or symptomatic bradycardia) without a func-tioning pacemaker; severe, uncontrolled tachyarrhythmias; acute decompensated heart failure; acute myocarditis or pericarditis; se-vere aortic stenosis, especially if symptomatic;systolic blood pressure <90 mmHg or>200 mmHg; acute pulmonary embolism or infarction; active bronchopscant lung disease,including asthma with ongoing wheezing or significant reactive airway disease; recent(<48 hours) use of dipyridamole or dipyridamole-containing medications; and known hypersensitivity or allergy to the phar-macologic stress agent being considered.Key considerations - Press protocol flexibility

• Stress protocol flexibility

<BeginOfPara>O Exercise stress testing (treadmill, bicycle),in addition to pharmacologic stress, is enabled by the tracer's 110-minute half-life,particularly for patients able to achieve adequate workload.

• Patient selection

○ Additional patient selection considerations follow those of the SNMMI PET MPI Appropriate Use Criteria document [12].

○ For breastfeeding, it is recommended that the infant is breastfed just before the first injection to maximize the time between the injection and the next feed. Breast milk may be expressed and fed to the infant via a bottle for the following 12 hours to help minimize the interruption and prolonged contact between the infant and the mother[41]. Temporary breastfeeding discontinu-ation for≥12 hours postinjection is rec-ommended, with milk expressed and discarded during this period to minimize infant radiation exposure.

○While there are no specific societal guide-lines regarding this, it is recommended to maintain a distance of≥2 m from infants,children, or pregnant women for 10 hours post the final ${}^{18} F$ -flurpiridaz injection. This time frame corresponds to approximately 5 half-lives of the radiotracer, resulting in<5% residual activity.

○ Preferred over SPECT MPI in specific pop-ulations, such as women, obese patients,and those with small left ventricles, due to its superior spatial resolution and diag-nostic accuracy.

○ ${ }^{18}$ F-flurpiridaz has not been evaluated in pediatric patients.

• Tracer logistics

● Unit-dose production via regional cyclotrons eliminates generator dependency or need for an on-site cyclotron.

QUALIFICATIONS AND RESPONSIBILITIES OF PERSONNEL

The introduction of the novel radiotracer$\stackrel{\text { 18F-flurpiridaz has further enhanced the capa- }}$ bilities of cardiac PET perfusion imaging as detailed in this document. The use of this radiotracer thus necessitates a high level of expertise and responsibility from the healthcare team involved in the execution of each study.The following section outlines the qualifications and responsibilities of personnel performing cardiac PET stress testing using $\stackrel{\text { 18F-flurpiridaz }}$ . It should be noted that these may not be univer-sally applicable, as national legislation and institutional practices can vary, e.g. for stress agent administration or cardiac stress test supervision.

Qualifications of personnel

1. Nuclear cardiology laboratory director

● Specialized training: The nuclear cardiology laboratory director should be a board-certified nuclear medicine physician,board-certified radiologist, or a board-certified cardiologist with Core Cardiovas-cular Training Statements (COCATS) Level III certification in nuclear cardiology, requiring additional training beyond the 3-year car-diovascular fellowship dedicated to acquiring specialized knowledge and com-petencies in performing, interpreting, and training others to perform cardiac PET.Physicians certified by the American Board of Radiology (ABR) or the American Board of Nuclear Medicine (ABNM) have substantial knowledge of general PET/CT image acqui-sition and postprocessing, including the design of PET/CT protocols and the use of diagnostic workstations. However, to ach-ieve specific competency in cardiac PET/CT,physicians require dedicated training and hands-on experience in cardiac PET/CT

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protocols and interpretation. Certification by the Certification Board of Nuclear Cardiology(CBNC) is recommended to demonstrate expertise and competence in performing,interpreting, and overseeing nuclear cardi-ology procedures, and to ensure adherence to established standards of clinical practice.

● Radiopharmaceuticals: The laboratory direc-tor must be well-versed in the sourcing,handling, and administration of ${ }^{18}$ F-flurpir-idaz. They should also be proficient in the interpretation of PET scan results, with a deep understanding of the pharmacokinetics and imaging characteristics of ${ }^{18}$ F-flurpiridaz.

● Continuing education: Ongoing education and training are crucial for staying updated with advancements in PET imaging tech-nology and radiopharmaceuticals, including the use of 18F-flurpiridaz. Dedicated training in the interpretation of 18F-flurpiridaz PET images is required, as these images exhibit characteristics distinct from those of other cardiac PET tracers; therefore, practitioners should collaborate with experienced readers and participate in structured educational activities such as clinical case review ses-sions or targeted webinars to ensure accu-rate image interpretation and minimize the risk of misdiagnosis.

2.Interpreting physician

● Educational background: The supervising nuclear medicine attending or radiologist must have completed a residency program,and the supervising cardiologist a dedicated fellowship. They should be board-certified by relevant authorities such as the ABR,ABNM, or the American Board of Internal Medicine (ABIM) in cardiovascular medicine and be COCATS Level II or Level III certified in nuclear cardiology, with certification from the CBNC recommended.

● Specialized training: Additional specialized training in cardiac imaging, particularly PET imaging, is ideal. This may include fellow-ships focused on advanced cardiac imaging or cardiovascular nuclear medicine. Physi-cians performing or supervising exercise or pharmacologic stress testing as part of car-diac PET/CT should meet the qualifications outlined in the American College of Cardi-ology/American Heart Association Clinical Competence Statement on Stress Testing[42]. Physicians supervising stress-induced examinations should have appropriate training in advanced cardiovascular life support and hold Advanced Cardiac Life Support(CLS) certification.

● Continuing education: Ongoing education and training are crucial for staying updated with advancements in PET imaging tech-nology and radiopharmaceuticals, including the use of ${}^{18}$ F-flurpiridaz.

3. Nuclear medicine technologists

● Educational requirements: The nuclear medicine technologist should hold an associate or bachelor's degree in nuclear medicine technology. They must possess certification from the Nuclear Medicine Technology Certification Board(NMTCB), or an equivalent credential issued by a licensing organization recognized by the relevant regulatory body in their country, in accordance with local requirements.

● Technical skills: They should possess strong technical skills in operating PET/CT imaging equipment and administering radiotracers.Given the novel nature of ${ }^{18}$ F-flurpiridaz,technologists must be trained specifically in the preparation, dosage calculation, and administration of this agent.

● Continuing education: Ongoing education and training are crucial for staying updated with advancements in PET imaging tech-nology and radiopharmaceuticals, including the use of 18F-flurpiridaz.

4. Cardiac stress test supervising provider

● Education: Healthcare providers supervising the cardiac stress test may be a physician, or a physician in training, physician assistant(PA), nurse practitioner (NP), or registered nurse (RN) under physician supervision and with the physician available as needed. The physician, PA, NP, or RN should have completed an accredited program and be certified and licensed to practice medicine.Experience in cardiac care or critical care is highly desirable.

● Certifications: ACL certification is manda-tory due to the potential risks associated with stress testing.

● Clinical experience: The physician, PA, NP,or RN should have extensive experience in managing patients undergoing stress testing, including the ability to recognize and respond to adverse reactions. Knowl-edge of ${}^{18} F$ -flurpiridaz pharmacology,administration protocols, and proper pro-cedures for handling spills is essential.

5. Pharmacists

● Specialized knowledge: If a pharmacist is involved in cardiac PET stress testing, they should have specialized knowledge in

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nuclear pharmacy, particularly in the preparation and dispensing of radiophar-maceuticals. Familiarity with the pharma-codynamics, dosing, and potential interactions of $^{18}$ F-flurpiridaz is crucial.

● Collaboration and consultation: Pharmacists may be required to collaborate with nuclear medicine physicians and technologists.They should be available for consultation regarding drug interactions of not just ${}^{18}$ F-flurpiridaz but also stressor agents with pa-tient's medications and patient-specific considerations.

6. Nuclear medicine physicists

● Educational requirements: Nuclear medi-cine physicists must have a graduate degree(Master's or PhD) in medical physics, radio-logic physics, physics, or a closely related physical science or engineering discipline.Additionally, formal coursework in biolog-ical sciences is required, including subjects such as biology, radiation biology, anatomy,and physiology.

● Clinical experience: Documented clinical experience in a nuclear medicine environ-ment, inclusive of PET, is required. This is essential and typically acquired through structured training programs such as in-ternships, residencies, or postdoctoral pro-grams in a clinical setting. The physicist should be able to demonstrate competence to practice independently in nuclear medi-cine physics, as evidenced by prior educa-tion and clinical experience.

● Certification: Certification is strongly rec-ommended as it demonstrates expertise and competency in the field. While it may not be universally mandated by all institutions, it is considered best practice and may be required by local, state, or national regula-tions. In the United States, nuclear medicine physicists may obtain board certification via the American Board of Radiology and the American Board of Science in Nuclear Medicine.

Responsibilities of personnel

1. Supervising physician

● Patient evaluation: The nuclear medicine physician, radiologist, or cardiologist is responsible for evaluating patients to deter-mine the appropriateness of cardiac PET stress testing with { }^{18}F-flurpiridaz, considering factors such as medical history, current medications, and potential contraindications.

• Supervision of the procedure: They should oversee the procedure, ensuring that the radiotracer is administered correctly and the imaging process is carried out safely and effectively.

● Interpretation of results: The physician is responsible for accurately interpreting car-diac PET results and integrating these with clinical data to deliver a comprehensive diagnosis that guides and optimizes the pa-tient's medical care.

2. Nuclear medicine technologists

● Preparation and administration: Technolo-gists are responsible for the preparation and administration of 18F-flurpiridaz, including ensuring the correct dosage and proper in-jection technique.

● Equipment operation: They must operate the PET imaging equipment, ensuring optimal image quality and patient safety.Technologists are also responsible for qual-ity control, ensuring correct PET/CT cor-egistration, initial verification of time-activity curve contours and of potential im-age artifacts as well as maintaining and calibrating the equipment.

● Patient monitoring: Technologists may be tasked with monitoring patients throughout the procedure, identifying any adverse re-actions, and communicating these to the supervising physician.

3. Cardiac stress test supervising provider

● Preprocedure preparation: The supervising healthcare provider (physician, PA, NP, or RN) should provide a procedure overview to the patient, obtain a signed informed con-sent, prepare the patient for the stress test,and obtain vital signs.

● Monitoring during stress testing: During the stress test, the supervising healthcare pro-vider should monitor vital signs, conduct the exercise protocol or administer the stressor agent, and respond to any complications.

● Postprocedure care: Nurses are responsible for postprocedure care, including moni-toring for delayed adverse reactions and providing patient education and discharge instructions.

4. Pharmacists

● Radiopharmaceutical preparation: Pharma-cists may collaborate with nuclear technol-ogists and nurses to ensure accurate dosing and safety verification of stressor medica-tions and reversal agents when adminis-tered,manage potential drug interactions,

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and provide expert consultation to the nu-clear cardiology laboratory. They are also responsible for ensuring compliance with regulatory standards and maintaining sterile preparation environments.

5. Nuclear medicine physicists

● Safety and radiation protection: Nuclear medicine physicists oversee the safe opera-tion of imaging equipment, including PET scanners. They ensure radiation protection for patients, staff, and the public by imple-menting, monitoring, and maintaining radi-ation safety protocols. Responsibilities include verifying shielding, supervising the handling and disposal of radioactive mate-rials, ensuring compliance with regulatory requirements, and overseeing the imple-mentation of safety procedures.

● Technical expertise and quality control:Physicists are responsible for the calibration,maintenance, and quality control of the PET system. They conduct routine quality assur-ance, monitor system performance, identify and resolve equipment malfunctions, and optimize imaging protocols to minimize radi-ation exposure while maintaining diagnostic accuracy. Additional duties include applying expertise in image processing, data analysis,troubleshooting technical or clinical anoma-lies, contributing to the development and validation of new imaging techniques, and staying current with advances in nuclear medicine physics through continuing educa-tion and certification.

PROTOCOL

1. Patient preparation

Patient preparation includes a 4 hours fast (water permitted) prior to imaging and smoking cessation for at least 12 hours. In patients un-dergoing pharmacologic stress testing, caffeine and other methylxanthine-containing products should be discontinued for at least 12 hours,ideally 24 hours, and theophylline-containing medications for 48 hours. Antianginal medica-tions such as beta-blockers, calcium channel blockers, and nitrates may be discontinued at the discretion of the referring physician [11,43].

2. Facilities, equipment

● Rooms where patients are located during and after injection of ${ }^{18} ~F$ -flurpiridaz should be appropriately shielded to account for

both the high-energy 511 keV photons pro-duced by PET radiopharmaceuticals and the extended 110-minute half-life of ${}^{18}$ F, leading to patients remaining a source of radiation for a significant period after injection [44].Therefore, scanner and uptake rooms,waiting areas, and any spaces where pa-tients may spend time postinjection must be designed with adequate shielding to ensure radiation safety for staff and the public in accordance with federal and professional guidelines.

● A designated patient toilet should be avail-able with radioactive signage posting.

● The PET/CT scanner should be equipped with cardiac (electrocardiogram [ECG])gating (respiratory gating optional).

● Stress test monitoring equipment, including 12-lead electrocardiograph and sphygmo-manometer, is required in the PET imaging and stress lab.

● An ACLS cart should be readily available on-site for potential complications.

3. Radiotracer delivery

${ }^{18}$ F-flurpiridaz has a 110-minute half-life,enabling unit dose production at regional cyclotrons and subsequent delivery to nuclear cardiology laboratories, similar to ${ }^{18}$ F-fluo-rodeoxyglucose, and obviating the need for an on-site cyclotron or generator.

4. Radiotracer dosage

The doses used in the ${ }^{18}$ F-flurpiridaz phase III clinical trials were 92.5-111 MBq (2.5-3.0 mCi) for the rest acquisition, 222-240.5 MBq (6.0-6.5 mCi)for pharmacologic stress (1:2 rest-to-pharmacologic stress ratio) with a≥30 minute interval between rest and stress dose injections,and 333-351.5 MBq (9.0-9.5 mCi) for exercise stress (1:3 rest-to-exercise stress ratio) with a≥60 minute interval between rest and stress dose injections $[15,20]$ .

5. Stress testing and image acquisition

•Patients are typically asked to lay supine with arms above the head for the PET/CT scan.

● A topogram (scout) is first performed to localize the heart and position acquisition boundaries. Then, a low-dose CT is per-formed for attenuation correction purposes.

● For rest images, list-mode acquisition begins 10 seconds before radiotracer injection and continues for 15 minutes if the patient is

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scheduled for pharmacologic stress(Figure 1), or for 10 minutes if exercise stress(Figure 2) is planned.

● Pharmacologic stress agents(adenosine,regadenoson, or dipyridamole) are adminis-tered per established guidelines(Figure 1)[43]. An intravenous line is established, often with a dual-port Y-connect, to facilitate the administration of both the pharmacologic stress agent and 18F-flurpiridaz. The radio-tracer is injected at peak hyperemia, the timing of which depends on the specific protocol and vasodilator agent used. For pharmacologic stress imaging, list-mode acquisition should commence 10 seconds prior to 18F-flurpiridaz injection and continue for 15 minutes, following a minimum interval of 30 minutes from the rest injection.

● Exercise stress follows the Bruce or modified Bruce protocol, or bicycle exercise protocol,with tracer injection at peak stress(Figure 2).The patient exercises on a treadmill or bi-cycle with gradually increasing intensity while heart rate and blood pressure are monitored. 18F-flurpiridaz is injected intra-venously at peak exercise, which is

determined by reaching the target heart rate(≥85% of age-adjusted maximal heart rate)or maximal exertion. After 18F-flurpiridaz injection, the patient typically continues to exercise for an additional 1 to 2 minutes to enhance tracer uptake. Imaging is typically initiated 15-25 minutes after the stress in-jection, using a 10-minute list-mode acqui-sition protocol, and following a minimum interval of 60 minutes from the rest injection.

● List-mode acquisition of PET data is preferred, recording each detected event individually along with its precise time-stamp. This allows for extremely high tem-poral resolution-down to milliseconds.After acquisition, these event records can be retrospectively grouped into any desired time intervals for image reconstruction or analysis. List-mode acquisition is particu-larly advantageous for dynamic PET studies,where tracer kinetics over time are analyzed, and for situations where motion correction or retrospective gating is needed.

● CT attenuation correction is performed per institutional PET/CT protocols using low-

 Figure 1. 18F-flurpiridaz standard protocol for pharmacologic stress imaging.(A) For rest imaging, a scout is obtained followed by a CTAC scan, radiotracer administration, and rest PET. Prior to pharmacologic stress, residual frame(s) of sufficient duration, as determined by the software method adopted, should be acquired to enable residual activity correction. Pharmacologic stress with regadenosen, adenosine, or dipyridamole should be conducted according to the manufacturer's instruction. If the patient remains in the PET/CT scanner between rest and stress imaging, the stress CTAC scan may be performed either after or before stress PET imaging, or alternatively, the rest CTAC scan may be used for attenuation correction of both rest and stress PET images. If the patient gets off the scanner prior to stress imaging, scout and CTAC must be obtained prior to residual activity measurement. As for all PET radiopharmaceuticals used for rest and stress MBF measurement, image acquisition should start prior to probe delivery to the heart in order to avoid missing early tracer kinetics.(B) For both rest and pharmacologic stress, data are acquired in list-mode for 15 minutes and subsequently binned for analysis. Dynamic data derived from the initial 2.5-10 minutes, as specified by the software methodology, are utilized to generate time-activity curves and to quantify MBF. Data acquired between 5 and 15 minutes postinjection are used to produce static images for assessment of relative perfusion, as well as gated images for evaluation of LV volumes and function. CT, computed tomography; CTAC, computed tomography for attenuation correction;LV, left ventricular; m, minutes; MBF, myocardial blood flow; residual, residual activity measure from the rest ${}^{18} F$ -flurpiridaz in-jection prior to the stress ${}^{18} F$ -flurpiridaz injection to correct for residual activity; PET, positron emission tomography; s, seconds.

${}^{18}$ F-Flurpiridaz PET MPI and MBF Quantitation

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 Figure 2. ${}^{18}$ F-flurpiridaz standard protocol for exercise stress imaging. (A) For rest imaging, a scout is obtained followed by a CTAC scan,radiotracer administration, and rest PET. After a wait period, exercise stress is performed via a treadmill or bicycle protocol;at peak stress, the radiotracer is administered, and exercise continues for 1-2 minutes. Following patient recovery, a second set of scout and CTAC images are acquired, followed by stress PET imaging. (B) For both rest and exercise stress, data are acquired in list-mode for 10 minutes and subsequently binned for analysis. The entire 10-minute dataset is used to produce static images for assessment of relative perfusion, as well as gated images for evaluation of LV volumes and function. CTAC, computed tomog-raphy for attenuation correction; LV, left ventricular; m, minutes; PET, positron emission tomography; s, seconds.

dose, free tidal, or end-expiratory breathing protocols. CT acquisition parameters (e.g.tube current, voltage, slice thickness, rota-tion time, and pitch) should be chosen regarding the objective of the CT examina-tion (i.e. attenuation correction by PET/CT coregistration) [41]. CT scan parameters should be chosen such that patient radiation exposure is minimized, yet the dose is adequate to obtain the necessary information.

o For pharmacologic stress protocols, a topogram is first acquired, followed by an attenuation correction CT scan prior to rest ${}^{18}$ F-flurpiridaz imaging(Figure 1).Immediately prior to the stress portion of the study, residual frame(s) of sufficient duration-depending on the MBF quanti-tation method and software being used-are obtained for residual activity correction. After vasodilator stress and acquisition of stress ${}^{18}$ F-flurpiridaz im-ages, a second attenuation correction CT may be performed. According to institu-tional preferences, the second attenuation correction CT may be performed before stress ${}^{18}$ F-flurpiridaz images, or in some cases, the rest CT used for attenuation correction of stress ${}^{18}$ F-flurpiridaz images

(provided the patient is not moved from the scanner between rest and stress imaging).

o For exercise stress protocols, a topogram is first acquired, followed by an attenua-tion correction CT scan prior to rest ${}^{18}$ F-flurpiridaz imaging (Figure 2). After exer-cise stress, a second topogram and atten-uation correction CT are performed before acquiring stress ${ }^{18}$ F-flurpiridaz images.

● Continuous monitoring and immediate availability of advanced cardiac life support are required throughout the procedure to ensure patient safety. Aminophylline,theophylline, or caffeine must be immedi-ately available during all cardiac stress testing procedures utilizing vasodilator agents to allow for prompt reversal of serious or persistent adverse reactions [45].Cardiac resuscitation equipment must be available and trained personnel present during stress testing.

6. Image reconstruction and processing/postprocessing

● The static and ECG-gated images are recon-structed using the last 10 minutes of the acquisition. For gated image reconstruction,

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  Figure 3. PET/CT registration. Case-example of a 54-year-old female where ${}^{18}$ F-flurpiridaz PET-CT misregistration at stress led to an artifactual reversible perfusion defect appearance in the anterior and lateral walls. The patient had no significant disease in the LAD and RCA distributions and only a 34% LCX stenosis by quantitative invasive coronary angiography. The high spatial reso-lution of 18F-flurpiridaz PET may magnify misregistration errors; careful attention must be given to all standard PET/CT MPI quality control measures. CT, computed tomography; LAD, left anterior descending; LCx, left circumflex; MPI, myocardial perfu-sion imaging; PET, positron emission tomography; RCA, right coronary artery.

it is recommended to use 16 bins per R-R interval(i.e. per cardiac cycle); however, 8 bins is also acceptable. The dynamic images,used to quantify MBF, are generated from data collected during the first 2.5-10 minutes of the 15-minute rest and pharmacologic stress acquisition, depending on the specific method employed. Dynamic PET images with sequential short timeframes are necessary for sampling of the arterial blood activity and enabling accurate MBF quanti-tation. For rest and pharmacologic stress dynamic PET images, list-mode data can be

binned into 26 scan sequences of 15 x 10 seconds,5 x 30 seconds,5 x 60 seconds, and 1 x 300 seconds(amounting to 900 seconds[15 minutes] total)[21,37,39], though this may vary depending on the camera type. For exercise stress images, static perfusion im-ages reconstructed from the entire acquisi-tion are generally sufficient for clinical interpretation; however, acquisition in list-mode is recommended to enable post-processing review and correction of motion artifacts, which is essential for maintaining optimal image quality.

${}^{18}$ F-Flurpiridaz PET MPI and MBF Quantitation

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A. No RAC

 B. With RAC

 Figure 4. Residual activity correction. In same-day rest-pharmacologic stress ${}^{18}$ F-flurpiridaz PET/CT MPI protocols, residual ac-tivity correction(RAC) from the rest dose injection must be corrected prior to the stress dose injection in order to avoid over-estimation of stress myocardial blood flow and MFR values. Time-activity curves without(A) and with(B) RAC. CT, computed tomography;LAD,left anterior descending;LCx,left circumflex;MFR,myocardial flow reserve;MPI,myocardial perfusion imaging;PET, positron emission tomography; RCA, right coronary artery.

● As $^{18}$ F-flurpiridaz has already distributed in the myocardium at the time of imaging,stress MBF and ensuing MFR cannot be calculated using conventional compartment modeling following exercise stress.

● The physical and physiological characteris-tics of ${}^{18}$ F-flurpiridaz also allow to repeat imaging within minutes in cases where the image quality is compromised, without additional radiation exposure from the radiopharmaceutical or need for repeat stress testing.

● Both rest and stress acquisitions are cor-rected for attenuation using low-dose CT.Appropriate alignment of the CT and PET images is crucial to avoid misalignment ar-tifacts. Iterative reconstruction following manufacturer recommendation is prefer-able, with no or minimal postreconstruction filtering.

7.Quality control, pitfalls

● Adequate quality control of the PET/CT im-aging data is crucial to optimize clinical

results. The most common artifacts are due to patient, processing, and/or technical factors.

● Metallic implants, including the metallic components of pacemaker and implantable cardioverter defibrillator leads near the myocardium, may give rise to artifacts such as streaks or distortions on CT transmission images. Such artifacts on PET images usually result in either over- or under-estimation of the tracer uptake. Accordingly, caution is required during the CT-based attenuation correction procedures.

● Patient positioning is also important in avoiding artifacts. It is always important that the patient has the most comfortable and stable positioning possible to avoid movement artifacts during the exam. It is also important to ensure that the patient has their arms above their head to avoid trun-cation artifacts and poorer image quality.Excessive patient motion during PET acqui-sition may result in blurring, introduction of segmental perfusion defect, and inaccurate

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Figure 5. ${}^{18}$ F-flurpiridaz PET myocardial perfusion imaging. Case-example of a 75-year-old male with dyslipidemia who under-went exercise stress ${}^{18}$ F-flurpiridaz PET. Stress images are presented above the corresponding rest images in short-axis, vertical long-axis, and horizontal long-axis reconstructions. ${}^{18}$ F-flurpiridaz PET images demonstrate(i) a small area of moderate intensity decrease in tracer uptake at stress in the apex that is completely reversible;(ii) a medium-sized area of severe intensity decrease in tracer uptake at stress in the inferolateral wall that is partially reversible in the basal-sid inferior segments and completely reversible in the apical inferior segment. The invasive coronary angiogram demonstrated 54% left anterior descending artery, 75% left circumflex artery, and 100% right coronary artery stenoses. PET, positron emission tomography.

MBF quantitation. After each acquisition,the dynamic and static images should be reviewed, and if significant motion artifacts are present, the acquisition should be repeated.

● Registration between CT and PET data should be assessed by inspection of the fused display. Misregistration may introduce artifactual perfusion defect and decreased MBF, often affecting the anterior, antero-lateral, and lateral regions (Figure 3).

● Additional quality control is critical to ensure the accurate quantitation of MBF.Myocardial and blood pool regions are vali-dated, and correction for motion is applied if needed. The blood pool time-activity curves(TAC) should show a rapid increase followed by a rapid decrease in activity while the myocardial TAC should increase steadily after the blood pool peak activity followed by a plateau. Truncated, fragmented, or spread blood pool TAC can be seen with interstitial injections, impaired venous return, or

suboptimal injection and may lead to inac-curate MBF quantitation.

● Residual activity correction from rest images to pharmacologic stress images(Figure 1A)should be applied in same-day studies to avoid overestimation of stress MBF and ensuing MFR values(Figure 4)[21,37-39].

●Automated motion correction is now routinely applied in commercial software used for TAC processing and MBF quantita-tion and should also be used for ${}^{18}$ F-flurpir-idaz PET[46].

8. Quantitative myocardial perfusion and blood flow methods and software packages

Three published methods have been developed and validated for both automated relative perfu-sion assessment[37,47-49] and absolute MBF quantitation[16,21,37,39]. These techniques for ${}^{18}$ F-flurpiridaz PET[50] have been integrated into commercial software packages and are available from multiple vendors.

${}^{18}$ F-Flurpiridaz PET MPI and MBF Quantitation

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 Figure 6. Contribution of 18F-flurpiridaz PET myocardial blood flow metrics to unmask diffuse epicardial CAD. Case example of a 64-year-old male patient with diabetes mellitus who underwent pharmacologic stress 18F-flurpiridaz PET.18F-flurpiridaz PET with normal relative perfusion(stress images presented above the corresponding rest images in short-axis, horizontal long-axis, and vertical long-axis reconstructions)(A) and decreased stress myocardial blood flows and myocardial flow reserves in all coronary distributions(B). The patient had diffuse disease on invasive coronary angiography: 44% left main, 68% distal left anterior descending,46% proximal left circumflex,69% 1st obtuse marginal(OM),100% OM2,and 20% mid right coronary artery.CAD,coronary artery disease; PET, positron emission tomography.

9. Image interpretation

Interpretation of an ${}^{18}$ F-flurpiridaz PET study is akin to ${}^{13}$ N-ammonia and ${}^{18}$ Rb-chloride PET MPI(Figures 5 and 6). Perfusion images are reor-iented in the standard myocardial slices and displayed side-by-side using dedicated software.Left ventricular function and volume are assessed on ECG-gated images. Perfusion defects are characterized in terms of size, location,severity, and reversibility. Stress-induced perfusion defects are labeled as reversible when resting perfusion is normal and as fixed when they are unchanged from abnormal resting images. Reversible perfusion defects typically represent ischemia, while fixed perfusion defects may represent scar or hibernating myocardium. Typical attenuation artifacts frequently observed with SPECT MPI(e.g.d. diaphragmatic and breast attenuation arti-facts) are not observed with ${}^{18}$ F-flurpiridaz due to obligatory attenuation correction for PET.

- Visual and semiquantitative interpretation

Visual interpretation for all MPI studies should be categorized as(i) definitely normal,(ii) prob-ably normal,(iii) indeterminate,(iv) probably abnormal, or(v) definitely abnormal. Perfusion defects should be classified as reversible or nonreversible, and the defect intensity described as mild, moderate, or severe. Additionally, the myocardial territory involved should be reported,

and the defect size designated as small, medium,or large.

Perfusion can be scored for each segment of the standard 17-segment American Heart Association left ventricular model[51] on a 5-point visual scale:0= no defect;1= mild uptake reduction;2= moderate uptake reduction; 3= severe uptake reduction; and 4= absent uptake. Summed rest score(SRS) and summed stress score (SSS)represent the sum of all 17 segments for the corresponding acquisition, and summed differ-ence score (SDS) is the difference between SSS and SRS. Summed scores integrate the global extent and severity of perfusion defects, with SRS reflecting scar and/or hibernating myocardium and SDS representing ischemia. A summed stress score 0-3(<5% of the left ventricular [LV]myocardium) is considered normal; 4-7(~5%-10% of the LV myocardium) mildly abnormal; and≥8(>10% of the LV myocardium) moderately to severely abnormal [52].

Due to the high extraction fidelity of ${}^{18}$ F-flur-piridaz at elevated flow rates, this tracer allows detection of mild CAD on relative perfusion im-aging with corresponding subtle reductions in stress MBF and MFR[21]. This may reduce diag-nostic specificity by identifying hemodynamically insignificant CAD that was not previously readily detectable with ${}^{82}$ Rb-chloride or ${}^{13}$ N-ammonia.Thus, higher specificity in visual interpretation should be favored to avoid over-/mis-diagnosing flow-limiting epicardial CAD.

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● Normal variants: Nonreversible apical or apical inferior“perfusion defects” can be observed in the absence of underlying CAD and are due to partial volume effects related to physiological apical thinning and the high special resolution of 18F-flurpiridaz. These decreases in tracer uptake show normal wall motion on the gated study. Given the high extraction fraction of 18F-flurpiridaz, perfu-sion heterogeneity at high flow may be observed on stress acquisition. Comprehen-sive study interpretation integrating MBF data are therefore critical.

● Myocardial blood flow: Assessment of TAC quality is essential[53,54]. Coronary terri-tories with stenosis≥50% demonstrate lower stress MBF and MFR compared to territories perfused by normal coronaries[16]. Early analyses indicate that stress MBF may be superior to MFR for detection of epicardial CAD[21] and that stress MBF provides in-cremental diagnostic value over relative perfusion alone to unmask intermediate le-sions defined as 50%-69% stenosis. Further-more, the integration of regional relative perfusion and MFR through integrated myocardial flow reserve(iMFR) may identify focal and diffuse perfusion impairments,with focal metrics linked to obstructive CAD[55]. Regions showing“reversible perfusion defects," despite high stress MBF and MFR, may indicate variations or heterogeneity in perfusion distribution at elevated flow rates when significant epicardial CAD is not pre-sent. Global, territory, and segmental rest MBF, stress MBF, and MFR are assessed.Coronary territory reduction in stress MBF and MFR corresponding to a reversible perfusion defect is indicative of obstructive CAD. Cases of globally reduced stress MBF and MFR along with normal rest/stress perfusion may be indicative of suboptimal response to pharmacologic stress, severe multivessel epicardial disease with balanced ischemia, a combination of moderate multi-vessel and microvascular disease, or isolated coronary microvascular disease.

● Stress myocardial blood flow and myocardial flow reserve cutoffs: A comparative analysis of the three published methods of 18F-flur-ripidaz PET MBF quantitation indicates similar optimal thresholds to detect epicar-dial CAD(Table 1)[56]. For stress MBF, these were 1.6-1.9 mL/min/g for≥50% stenosis and 1.6-1.7 mL/min/g for≥70% stenosis, respec-tively, depending on the software package.For MFR, the optimal thresholds were 2.3-2.5 for≥50% stenosis and 2.1-2.2 for≥70%

Table 1. 18F-flurpiridaz stress MBF and MFR cutoff values to detect coronary artery disease

|Metric,by software|Value|Sensitivity|Specificity|PPV|NPV| |---|---|---|---|---|---| |SMBF CAD ≥50%|SMBF CAD ≥50%|SMBF CAD ≥50%|SMBF CAD ≥50%|SMBF CAD ≥50%|SMBF CAD ≥50%| |ECTb|1.7|65|66|35|87| |4DM|1.9|73|61|34|89| |QPET|1.6|65|65|34|87| |SMBF CAD ≥70%|SMBF CAD ≥70%|SMBF CAD ≥70%|SMBF CAD ≥70%|SMBF CAD ≥70%|SMBF CAD ≥70%| |ECTb|1.6|80|67|18|97| |4DM|1.7|79|71|20|97| |QPET|1.6|80|66|17|97| |MFR CAD ≥50%|MFR CAD ≥50%|MFR CAD ≥50%|MFR CAD ≥50%|MFR CAD ≥50%|MFR CAD ≥50%| |ECTb|2.5|70|57|31|87| |4DM|2.3|64|61|32|86| |QPET|2.5|68|59|31|87| |MFR CAD ≥70%|MFR CAD ≥70%|MFR CAD ≥70%|MFR CAD ≥70%|MFR CAD ≥70%|MFR CAD ≥70%| |ECTb|2.2|75|65|16|97| |4DM|2.1|71|70|18|96| |QPET|2.2|70|68|16|96|

CAD,corary artery disease; ECTb,Emory Cardiac Toolbox,Syntermed, Inc.; 4DM, Corridor4DM, INVIA, Medical Imaging Solutions, Inc. MFR, myocardial flow reserve; NPV, negative predictive value; PPV,positive predictive value; QPET, quantitative PET, Cedars-Sinai Medical Center; SMBF, stress myocardial blood flow.

Optimal cutoff values for 18F-flurpiridaz stress myocardial blood flow and myocardial flow reserve across ECTb, 4DM,and QPET software methods to detect epicardial CAD at different stenosis thresholds.(Reproduced with permission from Ref.[56]).

stenosis, respectively. These cutoffs have not been validated prospectively and may vary with age and with“real-world” adoption and application of 18F-flurpiridaz.

● Segmental myocardial blood flow assess-ment: The favorable characteristics of 18F-flurpiridaz,including the low positron energy of 18F[22,57], permit precise evaluation of segmental MBF, defined as the lowest segmental MBF metric using the 17-segment left ventricular American Heart Association model[21]. Segmental stress MBF and MFR provides superior diagnostic performance for detection of both CAD≥50% and≥70% ste-nosis compared to territory stress MBF and MFR[21]. This is particularly driven by the left anterior descending(LAD) distribution[21].

● Gated function: 18F-flurpiridaz PET imaging enables comprehensive assessment of LV function by quantifying resting and stress LV end-diastolic volume(LVEDV), end-systolic volume(LVESV), and ejection fraction(LVEF).Resting LVEF provides baseline systolic func-tion, while stress LVEF and LVEF reserve(defined as stress LVEF-rest LVEF) reflect

${}^{18}$ F-Flurpiridaz PET MPI and MBF Quantitation

17

hemodynamic responses to stress, with abnormal reserve(≤0%) indicating impaired contractile reserve associated with severe CAD. Global and regional wall motion and myocardial thickening are evaluated during stress to identify ischemia-induced abnor-malities, enhancing detection of flow-limiting stenoses.

● Attenuation CT: CT images are reviewed for a qualitative or quantitative assessment of coronary calcification and should be reported[58]. Furthermore, incidental findings such as lung nodules, lymphadenopathies, pleural effusions, or pericardial effusions, should also be noted and reported as incidental findings.

10. ${}^{18}$ F-Flurpiridaz PET MPI report

Reporting of ${}^{18}$ F-flurpiridaz PET study findings should be structured and include patient identi-fication, study indication/clinical history, radio-tracer dose, CT parameters(e.g. tube current,tube voltage) and radiation(e.g. dose-length product), detailed information on stress methods with patient symptoms, vital signs, and ECG findings, description of perfusion at rest and at stress,global, territory,and segmental MBF and flow-derived metrics at rest and at pharmacologic stress, global and regional left ventricular func-tion at rest and at peak stress, ancillary findings,CT observations including coronary calcification and incidental CT findings, and overall impres-sion. For more details on structured reporting of MPI studies, see the ASNC imaging guidelines/SNMMI procedure standard for PET nuclear car-diology procedures[52,59].

BIODISTRIBUTION AND DOSIMETRY

● The average radiation dose for 18F-flurpiridaz per unit of administered activity is given in

Table 2. The critical organ after a rest injection of ${}^{18}$ F-flurpiridaz is the kidney(.066 mSv/MBq),while for both pharmacologic and exercise stress it is the heart(.090 mSv/MBq). Radiation dose information for other organs has been published for rest[34] and stress[35] injections of ${}^{18}$ F-flurpiridaz.

● The estimated radiation dose from a one-day rest/stress protocol using representative administered activity[15,35] is given in Table 3.The effective radiation doses for ${}^{18}$ F-flurpiridaz PET MPI are approximately 6.33 mSv for rest plus adenosine stress and 7.07 mSv for rest plus exercise stress. These are comparable to the 7 mSv effective dose of a standard 370 MBq(10 mCi) 18F-FDG administration[52,60]. On the basis of the observed mean effective dose, the maximum injected dose of 18F-flurpiridaz that may be administered without exceeding 10 mSv(1 rem) effective dose is 14 mCi(520 MBq) at rest, 15 mCi(539 MBq) in pharmaco-logic stress, and 19 mCi(685 MBq) in exercise stress,respectively[35].

● It should be noted that CT attenuation correc-tion contributes to the radiation dose. Appro-priate CT protocols should be used to balance image quality and radiation dose for attenua-tion correction CT [58]. Choice of an appro-priate CT protocol with exposure of $<1 mSv$ (or dose-length product approximately 38.5 mGy·cm, using a cardiac-specific conver-sion factor k=.026 mSv·mGy-1 cm-1 derived from coronary CT angiography and coronary artery calcium scans[61]) [58,62] allows a total radiation exposure of $\leq 9 mSv$ , as per societal recommendations [63]. Of note, there are currently no validated estimated k-factors for converting dose-length products to mSv for attenuation correction CT scans. Using a lower conversion factor k=.015 mSv·mGy-1 cm-1 has been proposed [64].

|Organ|Absorbed dose per unit activity in whole body and critical organs from intravenous administration of 18F-Flurpiridaz in adults||| |---|---|---|---| |Organ|Rest|Pharmacologic stress (adenosine)|Exercise stress| |Heart wall|.048|.090|.039| |Kidneys|.066|.057|.027| |Total body|.012|.012|.012| |Effective dose (mSv/MBq)|.019|.019|.015| |Data extracted from Refs. [34,35].||||

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Table 3. Estimated radiation dose in whole body and critical organs for one-day rest/stress imaging with 18F-Flurpiridaz in adults

||Rest|Pharmacologic stress (adenosine)|Exercise stress|Rest + pharmacologic stress|Rest + exercise stress| |---|---|---|---|---|---| |Activity|||||| |MBq|102|231|342||| |mCi|2.76|6.24|9.24||| |Heart wall(mGy)|4.90|20.79|13.34|25.69|18.23| |Kidneys(mGy)|6.73|13.17|9.23|19.90|15.97| |Total body(mGy)|1.22|2.77|4.10|4.00|5.33| |Effective dose|1.94|4.39|5.13|6.33|7.07| |(mSv)||||||

Data extracted from Refs.[34,35].

POTENTIAL PROTOCOL MODIFICATIONS

● Dobutamine stress

Dobutamine stress testing with 18F-flurpiridaz PET imaging has not yet been specifically studied in clinical trials but is expected to perform simi-larly to other PET(and SPECT) MPI radiotracers.The United States Food and Drug Administration(FDA) approval and published guidance indicate that 18F-flurpiridaz can be used with both exercise and pharmacologic stress, including vasodilators and dobutamine, due to its favorable physical properties and imaging characteristics. Dobut-amine stress is indicated for patients who cannot perform exercise stress testing and also have contraindications to vasodilator agents, especially those with bronchospastic airway diseases,including severe chronic obstructive pulmonary disease, or those who have ongoing wheezing.

- Stress-first/Stress-only imaging

Societal guidelines recommend stress-first SPECT MPI for selected low-risk CAD patients,with rest imaging only if stress results are abnormal. This approach shortens study dura-tion, enhances patient satisfaction, reduces radi-ation exposure, and improves efficiency while preserving diagnostic and prognostic value[63,65]. An 18F-flurpiridaz stress-first approach is expected to offer similar or greater benefits, as PET MPI provides superior attenuation correction,potentially reducing artifacts and the need for resting acquisitions, especially in obese patients.Additionally, its ability to quantify stress MBF during pharmacologic stress may improve mul-tivesel disease detection. However, it is impor-tant to note that stress-only acquisition does not allow MFR quantitation, which holds significant prognostic value. In retrospective analyses, stress

MBF quantitation with 18F-flurpiridaz demon-strated superior diagnostic performance compared to MFR for detecting significant CAD[21]. Furthermore, when combined with relative perfusion assessment, stress MBF provided addi-tional diagnostic value, particularly in cases with 50%-69% coronary stenosis[21]. These findings further support a stress-first/stress-only(if normal) strategy of 18F-flurpiridaz PET cardiac imaging. Additionally, a low-dose stress(i.e. 2.5-3.0 mCi[92.5-111 MBq]) protocol is likely feasible.However, these require prospective validation.

- Acquisition timing and duration

The myocardial-to-blood activity ratio peaks around 2 to 3 minutes after 18F-flurpiridaz injec-tion, allowing static perfusion images to be generated from earlier frames. Additionally, with newer highly sensitive camera systems, acquisi-tion times could be significantly shortened without compromising image quality. Taken together, these changes could shorten the acquisition time, potentially matching the dura-tion of 82Rb-chloride and 13N-ammonia PET MPI as follows: for rest and pharmacologic stress im-ages, list-mode acquisition may be obtained over a 6-minute period. Dynamic images are generated by binning the data collected from 0 to 5 minutes,while static and gated images are derived by binning the data from 2 to 6 minutes. In the case of rest and exercise stress imaging, list-mode acquisition may be performed over a 4-minute period, with static and gated images subse-quently generated by binning the entire 4-minute dataset. Further studies are needed to assess the impact of these adjustments on diagnostic accu-racy and workflow efficiency.

The mandatory wait time of 15 minutes in the trial design protocols was used to account for the spillover from rest to stress images with a 1:2 rest:

${}^{18}$ F-Flurpiridaz PET MPI and MBF Quantitation

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pharmacologic stress dose ratio due to the half-life of ${ }^{18}$ F. While not yet evaluated clinically, if a higher rest-stress dose ratio is used, e.g. 1:3, the wait time may be decreased significantly, and likely eliminated altogether if a rest-stress dose ratio of 1:4 is used (for example 2.0-2.5 mCi [74-92.5 MBq] at rest and 8 mCi [296 MBq] at stress).

• Ultra-low dose protocol

Recent advances in digital PET scanners as well as long field-of-view and total body PET scanners,allow for high count rate imaging. These scanners may vastly increase the versatility of ${}^{18} F$ -flurpir-idaz protocols. Due to the longer half-life of ${}^{18}~F$ -flurpiridaz, total body PET scanners can be uti-lized to perform ultra-low dose imaging with standard timing or normal dose protocols with ultra-rapid imaging(as above). Indeed, with total-body PET scanners, ${}^{18} F$ -FDG imaging may be performed with 1 mCi or even lower activity with whole-body images, including dynamic images[66]. Moreover, this protocol has the potential to provide quantitative flow measurements not only in the heart, but also throughout the peripheral arterial and renal circulation using extremely low radiation dose[67]. However, there is no current published data on this with ${}^{18} F$ -flurpiridaz.

• Repeat imaging

Patient motion can significantly degrade image quality. Repeat imaging is feasible with 82Rb-chloride but requires an additional radiotracer dose or repeat stress testing (for stress motion).By contrast, as with 99mTc-labeled SPECT perfu-sion tracers, the longer half-life of ${ }^{18}$ F-flurpiridaz allows for immediate repeat imaging-within minutes-without the need for additional radio-tracer administration or repeat stress testing (for stress PET imaging) if patient motion compro-mises image quality. Consequently, rest or stress imaging can be promptly repeated following a suboptimal scan.

• Viability and sarcoidosis imaging

For assessment of myocardial viability or for cardiac sarcoidosis/inflammation, MPI is followed by ${ }^{18}$ F-FDG PET/CT imaging, typically on the same day. With ${ }^{18}$ F-flurpiridaz, these protocols may need to be modified to two-day perfusion and metabolic studies.

`18`F-FLURPIRIDAZ PET WORKFLOW`

Implementing $^{18}$ F-flurpiridaz PET protocols in nu-clear medicine necessitates a thorough and sys-tematic evaluation tailored to each clinical

Table 4. Essential ${}^{18}$ F-Flurpiridaz workflow considerations

|Table 4.Essential ${}^{18}$ F-Flurpiridaz workflow considerations|| |---|---| |Workflow element consideration|Description/summary| |Dose ordering|Plan schedules in advance; order doses as needed Consider flexibility by ordering multidose vials Allocate specific time slots considering protocol time requirements (e.g. pharmacologic vs exercise, rest-stress vs stress first) In centers without high volumes of cardiac PET,18F-flurpiridaz protocols must be integrated alongside oncology and other noncardiac studies on the same scanner Early morning slots could be repurposed for18F-flurpiridaz PET imaging| |Workflow for stress testing|Use vasodilators, treadmill, or dobutamine for stress testing; protocols may include combined rest and stress studies or stress-only studies| |Workflow for exercise Stress testing can occur in a separate lab|cover rate Lab longer half-life allows recovery time, reducing artifacts Review images immediately for motion artifacts Consider ability to repeat scans if needed, and impact on schedule Rotate technologists to minimize exposure| |Staff radiation exposure|Consider safety protocols to manage radiation dose|

practice. Essential workflow considerations(Table 4) include ordering the appropriate dose,scheduling patient appointments, planning spe-cific imaging protocols, managing scanner avail-ability, and coordinating with other procedures utilizing the PET scanner. Additionally, factors such as the anticipated volume of procedures and the potential radiation exposure to staff must be taken into account. Addressing these elements will ensure the effective integration of ${}^{18}$ F-flurpir-idaz into nuclear imaging workflows, optimizing both operational efficiency and patient care.

• Dose ordering

Practices may need to plan schedules in advance and order ${ }^{18}$ F-flurpiridaz doses as needed. This approach differs from the use of ${ }^{82}$ Rb-chloride or${ }^{13}$ N-ammonia, where radiotracers can be pro-duced essentially continuously throughout the day using a generator or tabletop cyclotron,allowing for on-demand availability. Ordering vials that contain multiple doses may offer greater flexibility than ordering single-unit doses.

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● Patient scheduling

When planning the PET scanner schedule,several factors must be considered. Early morn-ing slots, typically reserved for $^{18}$ F-FDG patients during their uptake period, could be repurposed for $^{18}$ F-flurpiridaz PET imaging. Additionally, in centers where no dedicated cardiac PET system is available, time slots may need to be allocated between oncology or other noncardiac cases to accommodate rest and/or stress $^{18}$ F-flurpiridaz scans. Unlike $^{82}$ Rb-chloride, or in some cases $^{13}$ N-ammonia, which may be conducted in one setting using a single patient positioning, $^{18}$ F-flurpiridaz imaging using published clinical trial protocols necessitates extra scanner time due to the longer rest-stress delays, which may require patient repositioning during pharmacologic stress.

• Workflow for pharmacologic stress testing

Stress testing, whether pharmacologic or exer-cise, is feasible with ${ }^{18}$ F-flurpiridaz. Depending on the protocol, options include combined rest and stress studies or stress-only (if the stress images are normal) studies. However, given the clinical relevance of MFRand the importance of coronary microvascular function evaluation as an indica-tion for PET MPI, vasodilator studies are antici-pated to predominate. Most protocols will likely involve a combined rest and vasodilator stress study with dynamic imaging and flow quantita-tion. This can be completed in a single session using a low-dose/high-dose approach, or in two separate sessions.

- Workflow for exercise stress testing

Workflows similar to 99mTc-labeled SPECT MPI could be adopted, where stress testing is con-ducted in the exercise laboratory with radiotracer administration at peak exercise. ${}^{18} F$ -flurpiridaz al-lows for exercise testing in a stress lab separate from the scanner. However, due to the longer half-life of the radiotracer and the higher energy(511 keV) photons, staff must maintain a safe dis-tance from the patient after radiotracer adminis-tration. The longer half-life also provides time for the patient to recover from the stress test, poten-tially reducing artifacts such as upward creep and breathing-related issues that can occur[68]. While waiting for PET scanner availability, patients may need to remain in a hot patient waiting room(lead-lined, similar to 18F-FDG protocols). If the exercise stress study results are normal, rest imaging can be avoided, thereby reducing radiation exposure for both the patient and staff.

Protocols involving exercise stress may be favored-at the expense of losing valuable MBF information-when concomitant evaluation of exercise capacity, blood pressure and heart rate responses, symptom reproducibility, and induc-ible conduction abnormalities or arrhythmias, are desired. This exercise stress approach is relevant for patients with known or suspected anomalous coronary arteries, where functional evaluation during exertion may identify the presence of ischemia related to anatomic variations.

- Potential need for repeat imaging

With ${ }^{18}$ F-flurpiridaz, unlike ${ }^{82}$ Rb-chloride or ${ }^{13} ~N$ -ammonia, there is an option to repeat the scan, for example, if significant patient motion occurs dur-ing image acquisition. Therefore, it is important to review images as soon as possible after the scan to check for motion-related artifacts. However, if repeat imaging (without repeat radiotracer injec-tion) is necessary, flow quantitation is no longer possible due to the loss of early tracer kinetics. In this setting, acquisition time may need to be increased to compensate for decay and lower count rate to avoid a degradation in image quality.

TECHNOLOGIST CONSIDERATIONS

Considering the physical characteristics of ${ }^{18}$ F-flurpiridaz PET, careful management of occupa-tional radiation exposure remains essential due to the close proximity required during patient care activities. This includes all nuclear medicine professionals involved in the procedure, e.g. nu-clear medicine technologist, supervising physi-cian/physician assistant/nurse practitioner, or nurse, depending on the state or institution.

The salient periods of occupational radiation exposure associated with ${ }^{18} ~F$ -flurpiridaz PET occur during the following patient interactions:radiotracer injection, the immediate post-injection period, and at the conclusion of the exam, when assisting the patient off the scanner,addressing personal needs, and providing post-imaging instructions. In summary, any instance where staff are in close contact with the patient during and after radiotracer injection should be considered a potential exposure risk.

For the administration of ${ }^{18}$ F-flurpiridaz, the use of an infusion pump with a saline flush is recommended over manual (hand) injection. This approach minimizes radiation exposure to staff,ensures a consistent injection technique, and supports accurate MBF measurements and MFR derivations from rest and pharmacologic stress studies.

${ }^{18}$ F-Flurpiridaz PET MPI and MBF Quantitation

21

During exercise stress testing, enhanced safety protocols must be implemented to further reduce the risk of contamination and inadvertent expo-sure. This includes securing IV lines and injection ports to prevent dismodgement due to patient movement on the treadmill. Whether using an infusion pump or manual injection, the entire injection apparatus (including extension tubing,bifurcated tubing, 3-way stopcock, and saline flush) should be assembled and tested prior to${ }^{18}$ F-flurpiridaz administration. Staff should be trained and proficient in the use of thick PET sy-ringe shields and all ancillary equipment, with practice sessions conducted before actual patient${ }^{18}$ F-flurpiridaz injections to ensure competence and minimize the risk of error during exercise.

To further minimize staff radiation exposure,the following best practices are recommended:

● Strictly apply the principles of time, distance,and shielding:

o Reduce the time spent near radioactive sources whenever possible.

o Increase the distance from the patient or radiopharmaceutical source, as exposure decreases rapidly with distance.

o Use appropriate shielding, such as lead bar-riers, leaded glass, and syringe shields, to protect staff from direct and scatter radiation.

● Implement technical and engineering controls:o Use automated or remote dispensing and injection systems when available to reduce direct handling of radiopharmaceuticals.

o Employ modified lead pot lids or shielded workstations to minimize hand exposure during dose preparation and withdrawal.

o Ensure high-energy radioactive waste con-tainers are conveniently located for imme-diate disposal of contaminated materials.

- Optimize workflow and scheduling:

o Rotate staff to limit cumulative exposure,especially in high-volume settings and with exercise stress testing, and schedule high-risk procedures during periods of lower oc-cupancy to reduce overall risk.

o As with all nuclear medicine procedures,regularly monitor and audit radiation expo-sure: conduct routine audits of radiation safety practices to identify and correct any lapses; provide ongoing formal training in radiation protection, emergency procedures,and safe handling of radioactive materials.

- Note that since ${ }^{18} ~F$ (and all PET radiotracers)emits high-energy $511 keV$ photons, these are

not effectively attenuated by personal protec-tive equipment (PPE) such as lead aprons, thy-roid shields, or leaded eyewear.

LIABILITY STATEMENT

This guideline summarizes the views of the SNMMI/EANM/ASNC/ACNM Committees and Councils. It reflects recommendations for which the SNMMI/EANM/ASNC/ACNM cannot be held responsible. The recommendations should be considered in the context of good practice in nuclear medicine and do not replace national and international legal or regulatory requirements.

#

René Packard is a consultant for GE HealthCare(less than $\$ 5000 per year) and receives a research grant from GE HealthCare (more than $\$ 5000 per year) and re-ceives a research grant from GE HealthCare (more than $\$ 5000 per year). Matthieu Pelletier-Galarneau is a consultant for Jubilant Radio-pharma and Pfizer (less than $\$ 5000 per year) and receives receives a research grant from Jubilant Radio-pharma (more than $\$ 5000 per year). Mouaz Al-Lallah is a consultant for GE HealthCare and Jubilant (less than $\$ 5000 per year) and receives research grants from Consultant for GE HealthCare and Siemens $(\$ 5000$ per year) and receives research grants from $\$ 5000$ per year). Sharmila Dorbala is a consultant for Pfizer and Medtrace (more than$\$ 5000$ per year) and receives research grants from Attralus, Pfizer, GE HealthCare, Siemens, and Bridgebio (more than $\$ 5000$ per year). Edward Miller is a consultant for Pfizer, BridgeBio (Eidos),GE HealthCare, and Synektik (less than $\$ 5000$ per year) and receives research grants from Eidos,Pfizer, Alnylam, ArgoSpect, and Siemens (more than $\$ 5000$ per year). Antti Saraste is a consultant for Astra Zeneca, Novo Nordisk, and Pfizer (less than $\$ 5000$ per year) and receives honoraria for lectures from Abbott, AstraZeneca, Bristol Myers Squibb, and Pfizer (less than $\$ 5000$ per year).

ACKNOWLEDGMENTS

The guidelines have been brought to the attention of the relevant SNMMI, EANM, ASNC, and ACNM Committees and Councils and the EANM National Societies of Nuclear Medicine in Europe as defined in the EANM statutes. The received comments and suggestions of the above-mentioned committees are highly appreciated and have been considered for this guideline.

The writing group gratefully acknowledges Erika Cha (UCLA) for contributions to Figures 1 and 2;

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Edward Somer, PhD (GE HealthCare) for assistance with Figures 3 and 6; C. David Cooke, MSEE(Syn-termed Inc.) for providing Figure 4; and Sara Sims,RN(SNMMI senior project manager) for help and guidance in the development of this document.

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