18F-BMS-747158-02 (Flurpiridaz F 18 / Flyrcado): A Comprehensive Report on a Novel Myocardial Perfusion PET Agent

1. Introduction to 18F-BMS-747158-02 (Flurpiridaz F 18 / Flyrcado)

18F-BMS-747158-02, more commonly known by its International Nonproprietary Name (INN) Flurpiridaz F 18 and marketed under the trade name Flyrcado, is a cyclotron-produced radioactive diagnostic agent developed for Positron Emission Tomography (PET) myocardial perfusion imaging (MPI).[1] This agent is indicated for use under both rest and stress conditions, induced either pharmacologically or through exercise, in adult patients with known or suspected coronary artery disease (CAD). Its primary purpose is the evaluation of myocardial ischemia and infarction.[1] Chemically, Flurpiridaz F 18 is a fluorine-18 (18F) labeled pyridaben derivative.[5] The incorporation of the 18F radioisotope is a critical feature, providing a physical half-life of approximately 109.7 to 109.8 minutes.[2] This characteristic offers distinct advantages over earlier PET MPI tracers.

The development of advanced MPI agents like Flurpiridaz F 18 is driven by the ongoing need to improve non-invasive cardiac diagnostics. Traditional PET tracers for MPI have often relied on short-lived isotopes, such as Rubidium-82 (82Rb) or Nitrogen-13 (13N) ammonia, which typically necessitate on-site production facilities (cyclotrons or generators), thereby limiting their widespread clinical availability.[7] Flurpiridaz F 18 addresses this limitation by utilizing the longer half-life of 18F. This extended half-life facilitates centralized production in regional cyclotrons and subsequent distribution to imaging centers as unit doses, similar to the established model for 18F-fluorodeoxyglucose (FDG).[7] Such logistical improvements significantly enhance the accessibility of advanced cardiac PET imaging.

PET MPI is widely regarded as the gold standard for the quantification of myocardial blood flow (MBF).[9] Flurpiridaz F 18 aims to further refine this standard by offering superior image resolution. The 18F isotope has a relatively short positron range in tissue (approximately 1.03 mm), which is considerably shorter than that of other common PET isotopes like 82Rb (positron range ~8.6 mm), 15O (as in H$_2$$^{15}$O, positron range ~4.14 mm), or 13N (as in $^{13}$NH$_3$, positron range ~2.53 mm). This physical property translates to intrinsically higher spatial resolution in the resulting PET images compared to these other agents, and also offers an improvement over the resolution typically achieved with 99mTc-based Single Photon Emission Computed Tomography (SPECT) MPI.[3] The introduction of Flurpiridaz F 18 thus represents a significant step towards making high-quality, quantitatively accurate cardiac PET imaging more broadly available for clinical use.[12]

The development of Flurpiridaz F 18 is a clear response to the inherent limitations of previously available MPI agents. The short half-lives of agents like 13N-ammonia and 82Rb impose significant logistical and cost burdens related to on-site production, restricting their use to larger, specialized centers.[7] While SPECT MPI is more widely accessible, it generally provides lower image resolution and has been shown in comparative studies to have lower diagnostic accuracy, particularly sensitivity, than PET.[3] Flurpiridaz F 18, by employing the ~110-minute half-life of 18F [2], allows for centralized manufacturing and unit-dose distribution.[1] This logistical advantage, combined with the superior image resolution conferred by the 18F positron's short range [3], positions Flurpiridaz F 18 to offer the high diagnostic quality of PET with greatly improved practical feasibility.

The combination of enhanced image quality, documented improvements in diagnostic accuracy (especially in patient populations that are challenging to image with SPECT, such as women and obese individuals) [11], and these logistical benefits suggests that Flurpiridaz F 18 could significantly broaden the clinical application and impact of PET MPI. The longer half-life not only aids distribution but also makes exercise stress testing more feasible, as there is sufficient time between tracer injection at peak stress and the subsequent imaging procedure.[1] Exercise stress is often preferred over pharmacological stress as it provides a more physiological assessment of cardiac reserve. Collectively, these attributes indicate that a larger cohort of patients, including those for whom SPECT imaging might yield suboptimal or equivocal results, could benefit from the enhanced diagnostic capabilities of PET MPI with Flurpiridaz F 18, potentially leading to more accurate diagnoses and improved patient management strategies.

2. Development History and Regulatory Milestones

The radiopharmaceutical Flurpiridaz F 18, initially identified by the code BMS-747158-02, was first designed and investigated by Bristol-Myers Squibb Medical Imaging as a novel agent for PET myocardial perfusion imaging.[5] Early preclinical research focused on characterizing its biodistribution, myocardial uptake, and imaging quality in various animal models.[10] These foundational studies demonstrated favorable properties, including superior uptake compared to 13N-ammonia in pig models, and its quantitative accuracy was validated against radioactive microspheres.[9] The fundamental mechanism of action, involving the inhibition of mitochondrial complex I (MC-I), was also elucidated during this early phase.[7]

Following its initial discovery phase, Lantheus Medical Imaging assumed responsibility for the development of Flurpiridaz F 18, guiding it through extensive Phase 1, Phase 2, and pivotal Phase 3 clinical trials.[1] Phase 1 human studies established the initial safety profile, radiation dosimetry, biodistribution patterns, and fundamental imaging characteristics of the tracer in humans.[8] Subsequent Phase 2 trials further evaluated its diagnostic performance, often in comparison to the widely used SPECT MPI techniques.[15]

Two major multicenter, open-label Phase 3 clinical trials were instrumental in establishing the efficacy and safety of Flurpiridaz F 18: NCT01347710 and NCT03354273 (the latter also referred to as the AURORA study).[1] These trials rigorously compared Flurpiridaz F 18 PET MPI against SPECT MPI, using invasive coronary angiography (ICA) as the reference standard for defining significant CAD. In 2017, GE Healthcare acquired the exclusive global commercialization rights for Flurpiridaz F 18 from Lantheus. GE Healthcare then spearheaded the funding and final stages of development leading to regulatory approval, with Lantheus remaining a collaborator in the development and subsequent commercialization efforts.[18]

A significant milestone was reached in September 2024, when the U.S. Food and Drug Administration (FDA) granted approval for Flyrcado (Flurpiridaz F 18) for PET MPI in adult patients with known or suspected CAD.[1] Following this approval, GE Healthcare announced the commercial launch of Flyrcado in the United States, anticipated to begin in early 2025, with plans for expanding availability thereafter.[14]

The developmental trajectory of Flurpiridaz F 18, from its inception at Bristol-Myers Squibb to its eventual FDA approval under the stewardship of GE Healthcare, with a critical period of advancement by Lantheus Medical Imaging, underscores the intricate, time-consuming, and often collaborative processes involved in bringing novel radiopharmaceuticals to the clinical forefront. This multi-organizational involvement, spanning over a decade from early publications around 2007-2009 [5] to the 2024 approval [1], reflects the substantial investment, specialized expertise, and perseverance required in this field. It also suggests that companies with a dedicated focus on imaging and diagnostics, such as Lantheus and GE Healthcare, may be particularly well-suited to navigate the complexities of late-stage development and commercialization for such specialized agents.

The FDA's approval of Flurpiridaz F 18 is a noteworthy event that may significantly influence the landscape of myocardial perfusion imaging. The agent’s favorable characteristics—including logistical advantages stemming from its longer half-life allowing unit-dose availability [1] and superior diagnostic performance, particularly in terms of sensitivity and image quality, compared to SPECT MPI as demonstrated in large Phase 3 trials [11]—are validated by this regulatory decision. This combination of enhanced diagnostic capability and improved practicality is poised to facilitate a broader adoption of PET MPI, especially in clinical settings that previously faced barriers to implementing PET technologies reliant on short-lived tracers. The approval has been described as heralding a "new era" or a "significant advancement" in cardiac imaging.[12]

3. Chemical and Radiopharmaceutical Properties

Flurpiridaz F 18 is a specifically designed molecule for PET imaging, possessing distinct chemical and radiopharmaceutical characteristics that are fundamental to its function as a myocardial perfusion agent.

Chemical Identity:

The agent is recognized by several names and identifiers:

• International Nonproprietary Name (INN): Flurpiridaz F 18 [1]
• Alternative Chemical/Code Names: 18F-BMS-747158-02 [1], BMS-747158-02 (often referring to the molecule or its non-radioactive form) [5], NMB58 [1], flurpiridaz F-18.[1]
• Trade Name: Flyrcado.[1]
• CAS Number: 863887-89-2 (for the F-18 isotopologue).[1]
• Molecular Formula: C$_{18}$H$_{22}Cl[^{18}$F]N$_2$O$_3$.[2] The notation [$^{18}F]explicitlyindicatesthepresenceofthefluorine−18radioisotope.∗∗∗MolecularWeight:∗∗Approximately367.8g/mol.[6,8,34]∗∗∗IUPACName:∗∗2−tert−butyl−4−chloro−5−[[4−(2−(^{18}F)fluoranylethoxymethyl)phenyl]methoxy]pyridazin−3−one.[2,34]∗∗∗SMILES(SimplifiedMolecularInputLineEntrySystem):∗∗CC(C)(C)N1C(=O)C(=C(C=N1)OCC2=CC=C(C=C2)COCC[^{18}F])Cl.[2,34]∗∗∗InChIKey:∗∗RMXZKEPDYBTFOS−LRFGSCOBSA−N.[2,34]∗∗∗ChemicalStructure:∗∗FlurpiridazF18isaderivativeofpyridaben.[5,6,9]∗∗RadiopharmaceuticalCharacteristics:∗∗∗∗∗Radionuclide:∗∗Fluorine−18(^{18}$F).[2]
• Half-life: The physical half-life of $^{18}Fis109.7−109.8minutes.[2,7,8]∗∗∗ModeofDecay:∗∗Fluorine−18decaysviapositron(\beta$+) emission.[2]

Radiosynthesis, Purity, and Stability:

The production of Flurpiridaz F 18 involves a multi-step process optimized for clinical use:

• Precursor: The synthesis typically starts from a tosylated precursor, specifically 2-tert-butyl-4-chloro-5-[[4-(2-tosyloxyethoxymethyl)phenyl]methoxy]pyridazin-3-one. This precursor itself is synthesized from mucochloric acid via a series of organic reactions.[34]
• Radiolabeling: The core of the radiosynthesis is the nucleophilic substitution of the tosyl group on the precursor molecule with [$^{18}F]fluoride.The[^{18}$F]fluoride is typically produced in a cyclotron via the $^{18}O(p,n)^{18}$F nuclear reaction from $^{18}$O-enriched water. The radiolabeling reaction is often facilitated using a phase-transfer catalyst, such as tetrabutylammonium bicarbonate (TBA-HCO$_3$), in an organic solvent like anhydrous acetonitrile, and is carried out at elevated temperatures (e.g., 95°C).[20] Automated synthesis modules, for example, the Modular Lab-PharmTracer (ML-PT) system, are employed to ensure consistency and adherence to Good Manufacturing Practice (GMP) guidelines.[34]
• Purification: After radiolabeling, the crude product is purified. Modern protocols often utilize solid-phase extraction (SPE) methods, for instance, using a tC18 cartridge, which is generally faster and simpler than traditional semi-preparative High-Performance Liquid Chromatography (HPLC).[20]
• Radiochemical Yield (RCY): Reported decay-corrected radiochemical yields are typically in the range of 50-60% [20] or, with optimized automated systems, 55-65%.[34]
• Radiochemical Purity (RCP): High radiochemical purity is consistently achieved, generally greater than 98% or 99% as determined by radio-HPLC.[20]
• Stability: Flurpiridaz F 18 formulated for injection is reported to be stable for at least 12 hours at room temperature without detectable decomposition.[34] It is supplied as a clear, colorless to yellow solution.[4]

The development of an efficient, automated, and often HPLC-free radiosynthesis protocol that delivers Flurpiridaz F 18 with high yield, exceptional purity, and good stability is paramount for its successful translation into widespread clinical practice. Such optimized radiochemistry is essential for GMP-compliant production, ensuring a reliable supply of the radiopharmaceutical for routine diagnostic use. These factors underpin its feasibility as a "unit dose" agent, capable of being produced at a central radiopharmacy and distributed to multiple imaging centers.

Table 1: Chemical and Radiopharmaceutical Properties of Flurpiridaz F 18

Property	Detail	Snippet Source(s)
Approved Name	Flurpiridaz F 18	1
Trade Name	Flyrcado	1
Alternative Names	18F-BMS-747158-02, BMS-747158-02, NMB58	1
CAS Number	863887-89-2	1
Molecular Formula	C$_{18}$H$_{22}Cl[^{18}$F]N$_2$O$_3$	2
Molecular Weight	Approx. 367.8 g/mol	6
IUPAC Name	2-tert-butyl-4-chloro-5-[[4-(2-($^{18}$F)fluoranylethoxymethyl)phenyl]methoxy]pyridazin-3-one \$	2 \
\	**Radionuclide** \	Fluorine-18 (^{18}$F) \$
\	**Half-life of Radionuclide** \	109.7 - 109.8 minutes \
\	**Mode of Decay** \	Positron (\beta$+) emission
Key Precursor for Synthesis	2-tert-butyl-4-chloro-5-[[4-(2-tosyloxyethoxymethyl)phenyl]methoxy]pyridazin-3-one	34
Typical Radiochemical Yield	55-65% (automated)	34
Radiochemical Purity	>98%	20
Stability (Formulated)	At least 12 hours at room temperature	34

This table serves as a foundational reference, consolidating the core chemical and radiopharmaceutical identifiers and characteristics of Flurpiridaz F 18. For medical researchers, clinicians, and radiopharmacists, this information is essential for accurate identification, literature review, and understanding the basic nature of the agent before exploring its complex biological interactions and clinical applications.

4. Mechanism of Action

The efficacy of Flurpiridaz F 18 as a myocardial perfusion imaging agent is rooted in its specific interaction with cellular components within cardiomyocytes and the physical properties of the fluorine-18 radionuclide.

Targeting Mitochondrial Complex I (MC-1):

Flurpiridaz F 18 is a structural analogue of pyridaben, which is recognized as a potent inhibitor of mitochondrial complex I (MC-1), also known as NADH:ubiquinone oxidoreductase. MC-1 is the first and largest enzyme complex in the mitochondrial electron transport chain, playing a crucial role in cellular respiration and ATP production.4 Flurpiridaz F 18 binds to MC-1 with high affinity; its inhibitory concentration (IC$_{50}$) against MC-1 in bovine heart submitochondrial particles (16.6 ± 3 nmol/L) is comparable to that of other known MC-1 inhibitors like rotenone, pyridaben (non-radioactive), and deguelin.23 This interaction is quite specific to MC-1. The selective accumulation of Flurpiridaz F 18 in the heart is further enhanced by the high density of mitochondria within cardiac muscle cells, which can constitute 20-30% of the myocardial intracellular volume.7

Uptake and Retention in Cardiomyocytes:

The uptake of Flurpiridaz F 18 into cardiomyocytes is a rapid process, characterized by a high first-pass extraction fraction from the blood, averaging around 0.94. Notably, this high extraction efficiency appears to be largely independent of blood flow rates across a physiological range.3 The initial uptake mechanism is thought to involve passive diffusion across the cardiomyocyte cell membrane, facilitated by the lipophilic nature of the compound.7 Once inside the cell, Flurpiridaz F 18 binds with high affinity to MC-1 within the mitochondria. This strong binding is responsible for the prolonged retention of the tracer within the myocardium. Studies in rat cardiomyocytes have indicated a very rapid time to half-maximal (t$_{1/2}$) uptake (approximately 35 seconds) and a slow washout, with the t$_{1/2}$ for efflux of F-18 BMS-747158-02 being greater than 120 minutes.8 Myocardial tracer binding has been observed to be stable for over 2 hours.19 Consequently, regions of viable myocardium with intact mitochondrial function and adequate perfusion will exhibit higher concentrations of Flurpiridaz F 18 compared to infarcted or severely ischemic areas where mitochondrial activity and/or blood flow are compromised.2

**Role of the $^{18}FIsotopeinPETImaging:∗∗Thefluorine−18(^{18}$F) isotope is integral to the imaging process. $^{18}Fdecaysbypositron(\beta$+) emission.2 When a positron is emitted, it travels a very short distance within the tissue (the mean positron range for $^{18}$F is approximately 1 mm 7) before it encounters an electron. This encounter results in an annihilation event, converting the mass of both particles into two 511 keV gamma photons, which are emitted in nearly opposite directions (180° apart). PET scanners are designed to detect these pairs of coincident gamma photons. By analyzing the lines of response from many such events, a computer algorithm reconstructs a three-dimensional image representing the spatial distribution and concentration of the $^{18}$F-labeled tracer within the body, in this case, the myocardium. The intensity of the signal in the reconstructed PET image is proportional to the local concentration of Flurpiridaz F 18, thereby reflecting regional myocardial perfusion and mitochondrial integrity.12 The approximately 110-minute half-life of $^{18}$F is considered optimal for many PET imaging applications. It is long enough to allow for complex radiosynthesis, quality control, transport from a centralized cyclotron facility to the imaging site, biological distribution of the tracer within the patient, and an adequate imaging window. Yet, it is short enough to minimize the patient's radiation exposure and allow for repeat studies if necessary.2

The mechanism of action of Flurpiridaz F 18, specifically its targeting of MC-1, implies that its uptake is not solely dependent on blood flow (perfusion) but also on the presence of biologically active mitochondria. This suggests that the tracer may provide information that extends beyond simple perfusion assessment, potentially offering insights into myocardial viability at the mitochondrial level. While the tracer is delivered to the myocardium in proportion to blood flow 2, its retention requires functional mitochondria for binding. In infarcted tissue, both blood flow and mitochondrial integrity are severely compromised, leading to minimal tracer uptake.2 However, in ischemic but still viable myocardium (such as in stunned or hibernating states), blood flow may be reduced, but mitochondria might retain some level of function. The tracer's accumulation in such regions could therefore provide a more nuanced assessment than a purely flow-dependent tracer, potentially reflecting the metabolic health of the cardiomyocytes.

A critical characteristic contributing to the diagnostic potential of Flurpiridaz F 18 is its high (average 0.94) and largely flow-independent myocardial first-pass extraction fraction.3 This property is crucial for ensuring a more linear and accurate relationship between the measured tracer uptake in the myocardium and the actual myocardial blood flow. This is particularly important under conditions of high flow, such as during pharmacological or exercise stress, where some other perfusion tracers may exhibit a "roll-off" effect (i.e., their extraction efficiency decreases at higher flow rates, leading to an underestimation of true perfusion). The ability of Flurpiridaz F 18 to maintain high extraction across a wide range of flow values, including the upper physiological limits encountered during stress 15, suggests its suitability for accurate quantification of MBF and myocardial flow reserve (MFR). This accurate quantification is vital for precisely assessing the hemodynamic significance of coronary stenoses and detecting ischemia, especially when flow differentials are most pronounced. This near-linear myocardial extraction is highlighted as a key feature.13

## 5. Pharmacokinetics

The pharmacokinetic profile of Flurpiridaz F 18 describes its absorption, distribution, metabolism, and excretion (ADME) following intravenous administration, which are critical determinants of its performance as an imaging agent.

**Absorption (Post-Intravenous Administration):**

Flurpiridaz F 18 is administered exclusively via intravenous injection, typically as a bolus.4 Following injection, radioactivity in the blood peaks rapidly, with observations indicating a peak at approximately 2.3 minutes.2 The initial phase of blood radioactivity, within the first 15 minutes post-administration, is predominantly associated with the parent compound, unchanged Flurpiridaz F 18. Subsequently, as metabolism occurs, its metabolites contribute increasingly to the radioactivity detected in the blood.2

**Distribution:**

The tracer undergoes rapid distribution to various tissues throughout the body. Approximately 10 minutes after the dose, notable percentages of the injected activity are found in the liver (around 19%), kidneys (around 9%), brain (around 8%), and the heart wall (around 3%).2 Despite the distribution to other organs, significant and preferential uptake occurs in the myocardium. For instance, studies in rats demonstrated myocardial uptake of about 3.1% of the injected dose per gram (%ID/g) at 10 minutes post-injection 20, while in mice, myocardial uptake was measured at 9.5% ± 0.5% ID/g at 60 minutes.23 Importantly, radioactivity within the heart wall is retained for at least one hour after administration, providing a stable window for imaging.4 Flurpiridaz F 18 exhibits favorable heart-to-background ratios, meaning the signal from the heart is substantially higher than that from adjacent tissues like the lungs and liver. This characteristic is crucial for clear image contrast and accurate delineation of the myocardium. For example, in rat studies, the heart-to-lung activity ratio was observed to increase from 4.7 to 10.2 between 1 and 15 minutes post-injection.10 In mice, at 60 minutes, heart-to-lung and heart-to-liver ratios were reported as 14.1 ± 2.5 and 8.3 ± 0.5, respectively.23 These high ratios minimize interference from surrounding organ activity.

**Metabolism:**

Flurpiridaz F 18 is subject to biotransformation in the body, leading to the formation of numerous polar metabolites.2 These metabolites begin to appear in the circulation approximately 30 minutes after the injection of the parent drug.19

**Excretion:**

The parent compound, Flurpiridaz F 18, and its various metabolites are eventually cleared from the bloodstream, typically within 48 hours post-administration.2 The primary route of excretion for the radioactivity is renal.10 Studies using tritium ($^3$H)-radiolabeled flurpiridaz (non-radioactive fluorine) indicated that following a single intravenous dose, approximately 63% of the administered radioactivity was recovered in the urine, with none of it being the unchanged parent drug. An additional 30% of the radioactivity was recovered in the feces, also with no unchanged flurpiridaz detected.2 This suggests extensive metabolism prior to excretion.

Specific Populations:

Pharmacokinetic studies have indicated that there are no clinically significant differences in the behavior of Flurpiridaz F 18 based on age, sex, body mass index (BMI), diabetic status, mild hepatic impairment (Child-Pugh Class A), or mild to moderate renal impairment (estimated glomerular filtration rate $\ge$19 to 89 mL/min).4 However, the impact of moderate to severe hepatic impairment (Child-Pugh Class B and C) or end-stage renal disease on the pharmacokinetics of Flurpiridaz F 18 has not been formally evaluated, and these conditions could potentially alter its disposition.4

The pharmacokinetic profile of Flurpiridaz F 18—characterized by rapid myocardial uptake, high first-pass extraction, sustained retention within the heart muscle, favorable heart-to-background ratios, and efficient clearance of metabolites—collectively supports its utility as an effective PET imaging agent. These properties allow for the acquisition of clear, high-contrast myocardial images within a practical timeframe after tracer administration.

The observation that Flurpiridaz F 18 exhibits predictable pharmacokinetic behavior across a broad range of common patient demographics and comorbidities (such as age, sex, BMI, diabetes, and mild/moderate organ impairment) is a significant advantage for its clinical application.[4] This consistency reduces the likelihood of needing dose adjustments or concerns about variable imaging performance in diverse patient populations, simplifying its use in routine clinical practice. Nevertheless, the absence of specific pharmacokinetic data in patients with severe hepatic or renal disease represents an information gap. Given that the liver is involved in the initial distribution and the kidneys are the primary route of excretion for metabolites, severe dysfunction in these organs could theoretically alter the tracer's pharmacokinetics and dosimetry. This warrants careful consideration or further investigation if Flurpiridaz F 18 is to be used in such patient groups.

6. Preclinical Evaluation

Extensive preclinical studies were conducted to characterize 18F-BMS-747158-02 (Flurpiridaz F 18) and establish its potential as a myocardial perfusion imaging agent prior to human trials. These evaluations involved various animal models and comparative assessments.

Biodistribution Studies in Animal Models:

Biodistribution studies in rats demonstrated that BMS-747158-02 achieved substantially higher myocardial uptake compared to the commonly used SPECT agent, $^{99m}$Tc-sestamibi, at both 15 minutes and 120 minutes post-injection. Furthermore, the uptake ratios of heart-to-lung and heart-to-liver were also significantly higher for BMS-747158-02, indicating better target-to-background contrast.5 At 10 minutes post-injection in rats, a high myocardial uptake of 3.1 %ID/g was observed, accompanied by low activity in the lungs (0.3 %ID/g) and liver (1.0 %ID/g), which is favorable for cardiac imaging.10 PET imaging studies performed in rats, rabbits, and nonhuman primates consistently showed clear and sustained cardiac uptake of BMS-747158-02, with minimal interference from lung activity and evidence of rapid liver clearance.5 In rat models of myocardial infarction, created by either permanent or transient coronary artery ligation, the resulting perfusion deficit zones were clearly delineated by BMS-747158-02 PET imaging, and these findings correlated well with ex vivo histological assessments of infarct size.5

Comparative Studies:

The performance of 18F-BMS-747158-02 was rigorously compared against established perfusion tracers:

• Versus $^{13}$N-Ammonia (Pig Model): In a pig model, 18F-BMS-747158-02 demonstrated higher activity ratios between the myocardium and surrounding tissues (blood, liver, and lungs) under both rest and stress conditions when compared to $^{13}$N-ammonia. Both tracers, however, showed high and homogeneous myocardial uptake.[9]
• Versus Radioactive Microspheres (Pig Model): The gold standard for blood flow measurement, radioactive microspheres, was used to validate the quantitative capabilities of 18F-BMS-747158-02 in pigs. Regional myocardial blood flow assessed by PET with 18F-BMS-747158-02 showed a strong correlation (r=0.88) and good agreement with the measurements obtained using microspheres. This correlation held over a wide physiological flow range (0.1 to 3.0 mL/min/g). Additionally, the extent of perfusion defects induced by coronary artery constriction, as measured by 18F-BMS-747158-02 PET, also correlated well with microsphere-defined defect sizes.[9]
• Versus $^{201}$Tl-Thallous Chloride and $^{99m}$Tc-Sestamibi (Isolated Rabbit Heart Model): In an isolated, perfused rabbit heart model, the net uptake of BMS-747158-02 in the heart increased proportionally with increasing coronary flow rates. This increase was more pronounced than that observed for either $^{201}$Tl or $^{99m}Tc−sestamibiundersimilarconditions.[5]∗∗MyocardialFirst−PassExtraction:∗∗Akeycharacteristicinvestigatedwasthemyocardialfirst−passextractionfractionof18F−BMS−747158−02.Studiesinisolatedperfusedratheartsrevealedahighand,importantly,flow−independentfirst−passextractionfraction,averaging0.94(StandardDeviation=0.04).[10,20,23]Thispropertyishighlydesirableasitsuggestsalinearrelationshipbetweentraceruptakeandactualmyocardialbloodflowacrossvaryingperfusionstates,whichisfundamentalforaccuratequantitativeassessmentofperfusion.TheconsistentandcompellingfindingsfromthesediversepreclinicalevaluationsacrossmultipleanimalspeciesprovidedarobustfoundationfortheclinicaltranslationofFlurpiridazF18.Thedemonstrationofhighmyocardialuptake,favorablebiodistributionleadingtogoodimagecontrast,accuratereflectionofperfusiondefects,strongcorrelationwithgold−standardbloodflowmeasurements(radioactivemicrospheres),andapparentadvantagesoverexistingclinicalagents(^{13}$N-ammonia, $^{99m}$Tc-sestamibi) in animal models collectively signaled its significant potential as a superior myocardial perfusion imaging agent. The particularly promising characteristic of a high and flow-independent extraction fraction further bolstered confidence in its ability to provide accurate quantitative perfusion data, justifying its progression into human clinical trials.

Table 2: Summary of Key Preclinical Findings for 18F-BMS-747158-02

Animal Model	Key Parameter Investigated	Comparison Agent(s)	Key Result/Observation	Snippet Source(s)
Rat	Biodistribution, Myocardial Uptake	$^{99m}$Tc-Sestamibi	Higher myocardial uptake and heart-to-background ratios for 18F-BMS-747158-02. Clear delineation of infarcts.	5
Isolated Rat Heart	First-Pass Extraction	None	High (avg. 0.94) and flow-independent first-pass extraction.	10
Rabbit (Isolated Heart)	Myocardial Uptake vs. Flow	$^{201}$Tl, $^{99m}$Tc-Sestamibi	Proportional increase in uptake with flow, greater than comparators.	5
Pig	Myocardial Uptake, Biodistribution, Quantitative MBF, Defect Sizing	$^{13}$N-Ammonia, Microspheres	Higher heart-to-background ratios vs. $^{13}$N-Ammonia. Good correlation (r=0.88) of MBF with microspheres. Good correlation of defect size with microspheres.	9
Non-human Primates	Cardiac Uptake, Clearance	None	Clear and sustained cardiac uptake, minimal lung interference, rapid liver clearance.	5

This table consolidates the diverse preclinical data, offering a quick overview of the animal models used, the key performance characteristics evaluated, and how Flurpiridaz F 18 performed, often in comparison to existing agents. These foundational studies were crucial in demonstrating the tracer's potential before human trials commenced.

7. Clinical Efficacy and Performance

Following promising preclinical results, Flurpiridaz F 18 underwent a comprehensive clinical development program, including Phase 1, Phase 2, and two pivotal Phase 3 trials, to evaluate its safety, dosimetry, and diagnostic efficacy in humans.

Summary of Phase 1 Clinical Trial Findings:

Initial first-in-human studies, such as the one reported by Maddahi et al. in 2011 8, established that Flurpiridaz F 18 is clinically safe and has an acceptable radiation dosimetry profile. These studies also confirmed that it provides high-quality PET images of myocardial perfusion under both exercise and pharmacological stress conditions.8 The kidney was identified as the dose-critical organ, which informed the maximum recommended administered activity in subsequent trials (520 MBq or 14 mCi).8

Phase 2 Clinical Trial Insights:

A Phase 2 clinical trial, also led by Maddahi and colleagues 8, provided further evidence of Flurpiridaz F 18's capabilities. This trial demonstrated improved diagnostic performance for CAD, enhanced image quality, and greater confidence of interpretation with Flurpiridaz F 18 PET compared to conventional $^{99m}$Tc-SPECT MPI in a population of patients with suspected CAD.15

Pivotal Phase 3 Clinical Trials (NCT01347710 and NCT03354273 - AURORA Study):

Two large-scale, prospective, multicenter, open-label Phase 3 trials were conducted to definitively assess the diagnostic efficacy and safety of Flurpiridaz F 18 PET MPI. Both trials compared its performance against $^{99m}$Tc-SPECT MPI, using invasive coronary angiography (ICA) as the reference standard to define significant CAD (typically $\ge$50% luminal stenosis).1 Participants in these trials underwent rest and stress imaging procedures with both Flurpiridaz F 18 PET and SPECT.

• NCT01347710 (First Phase 3 Trial - Published by Berman DS, Maddahi J, et al., JACC 2020): This trial enrolled 755 evaluable patients with known or suspected CAD.11
• Sensitivity: For the detection of $\ge$50% stenosis by ICA, Flurpiridaz F 18 PET demonstrated a sensitivity of 71.9%, which was significantly higher than the 53.7% sensitivity achieved by SPECT (p < 0.001).[11]
• Specificity: The specificity of Flurpiridaz F 18 PET was 76.2%, while SPECT specificity was 86.6%. In this particular trial, Flurpiridaz F 18 PET did not meet the prespecified noninferiority criterion for specificity when compared to SPECT.[11]
• Overall Diagnostic Performance: Despite the specificity finding, receiver-operating characteristic (ROC) curve analysis indicated that Flurpiridaz F 18 PET had superior overall discrimination for CAD compared to SPECT. This superiority was observed in the overall patient population as well as in important subgroups, including women, obese patients, and patients undergoing pharmacological stress (p < 0.001 for all comparisons).[11]
• Image Quality and Diagnostic Certainty: Flurpiridaz F 18 PET was found to be superior to SPECT in terms of image quality and the diagnostic certainty it provided to interpreters (p < 0.001).[11]
• Radiation Exposure: Patients received a significantly lower radiation dose with the Flurpiridaz F 18 PET protocol (mean effective dose of 6.1 ± 0.4 mSv) compared to the SPECT protocol (mean effective dose of 13.4 ± 3.2 mSv; p < 0.001).[11]
• NCT03354273 (Second Phase 3 Trial / AURORA Study - Published by Maddahi J, et al., JACC 2023): This trial specifically enrolled 578 evaluable patients with suspected CAD, thereby excluding those with previously known CAD, to further assess diagnostic efficacy.1
• Primary Efficacy Endpoints: The study's primary efficacy endpoints, which were based on sensitivity and specificity of Flurpiridaz F 18 PET compared against a prespecified threshold value, were met by two of the three blinded image readers.[15]
• Sensitivity (vs. SPECT): Flurpiridaz F 18 PET achieved a sensitivity of 80.3%, significantly higher than SPECT's sensitivity of 68.7% (p = 0.0003).[13]
• Specificity (vs. SPECT): In this trial, Flurpiridaz F 18 PET demonstrated a specificity of 63.8%, which was found to be noninferior to SPECT's specificity of 61.7% (p = 0.0004 for noninferiority).[13]
• Overall Diagnostic Performance: The area under the ROC curve (AUC) for Flurpiridaz F 18 PET was significantly higher than that for SPECT in the overall population (0.80 vs. 0.68; p < 0.001). This superiority was also maintained in the subgroups of women and obese patients (p < 0.001 for both).[17]
• Image Quality, Defect Size/Severity, and Diagnostic Certainty: Flurpiridaz F 18 PET was again found to be superior to SPECT in evaluations of perfusion defect size and severity, overall image quality, and diagnostic certainty (p < 0.001 for all).[15]
• Safety: Flurpiridaz F 18 was reported to be safe and well tolerated in this trial population.[11]

Performance in Specific Subgroups:

A consistent and clinically important finding across both Phase 3 trials was the superior diagnostic performance of Flurpiridaz F 18 PET in patient subgroups known to be challenging for SPECT imaging, notably women (due to breast attenuation artifacts) and obese patients (due to increased soft tissue attenuation).11 Current imaging guidelines often recommend PET MPI for such difficult-to-image individuals.3

The collective evidence from these rigorous Phase 3 trials consistently points to a significant advantage of Flurpiridaz F 18 PET in terms of sensitivity for CAD detection when compared to SPECT MPI. This enhanced sensitivity is a crucial clinical benefit, as it implies a reduced likelihood of missing true disease (i.e., fewer false-negative results). While the first Phase 3 trial raised some questions regarding specificity, the second trial (AURORA study, NCT03354273), which focused on a population with only suspected CAD, demonstrated non-inferior specificity to SPECT and confirmed superior overall diagnostic accuracy through ROC analysis.[15] This suggests that factors such as patient population characteristics (e.g., prevalence of disease, prior interventions) and potentially interpretive criteria might influence specificity outcomes. Some analyses suggest that the high resolution of Flurpiridaz F 18 PET may make it more sensitive to milder, albeit potentially clinically relevant, flow-limiting stenoses, which could be classified as false positives if a strict $\ge$50% stenosis cutoff is used without considering overall plaque burden or more subtle perfusion abnormalities.[13]

The consistent demonstration of superior performance in women and obese patients is particularly noteworthy. These patient groups frequently pose diagnostic challenges for SPECT MPI due to attenuation artifacts that can mimic or obscure true perfusion defects. PET imaging, with its inherent and more robust attenuation correction methodologies and higher energy photons, is less susceptible to these artifacts.[3] The ability of Flurpiridaz F 18 PET to provide more reliable diagnostic information in these cohorts directly addresses a significant limitation of SPECT and offers a more accurate imaging option for a substantial segment of the patient population undergoing cardiac stress testing.

Table 3: Overview of Major Clinical Trials for Flurpiridaz F 18 (NCT01347710, NCT03354273)

Feature	NCT01347710 (Berman DS, Maddahi J, et al. JACC 2020)	NCT03354273 (AURORA Study - Maddahi J, et al. JACC 2023)
Phase	3	3
Patient Population	755 evaluable; Known or Suspected CAD	578 evaluable; Suspected CAD (Known CAD excluded)
Primary Endpoints	Diagnostic efficacy (Sensitivity, Specificity) vs. SPECT, ICA as reference	Diagnostic efficacy (Sensitivity, Specificity) vs. prespecified threshold & SPECT, ICA as reference
Sensitivity (PET vs. SPECT for $\ge$50% stenosis)	71.9% vs. 53.7% (p < 0.001)	80.3% vs. 68.7% (p = 0.0003)
Specificity (PET vs. SPECT for $\ge$50% stenosis)	76.2% vs. 86.6% (Non-inferiority Not Met)	63.8% vs. 61.7% (Non-inferiority Met, p = 0.0004)
Overall Diagnostic Accuracy (ROC AUC PET vs. SPECT)	Superior for PET (p < 0.001)	Superior for PET (0.80 vs. 0.68; p < 0.001)
Performance in Women & Obese Patients	Superior for PET (p < 0.001)	Superior for PET (p < 0.001)
Image Quality / Certainty	Superior for PET (p < 0.001)	Superior for PET (p < 0.001)
Radiation Exposure (PET vs. SPECT)	6.1 ± 0.4 mSv vs. 13.4 ± 3.2 mSv (p < 0.001)	Similar significant reduction with PET
Overall Safety Conclusion	Safe and well tolerated	Safe and well tolerated
Snippet Source(s)	11	1

This table provides a direct comparison of the two pivotal Phase 3 trials, underscoring the key efficacy metrics and safety conclusions that formed the basis for the regulatory approval of Flurpiridaz F 18.

8. Safety Profile and Tolerability

The safety and tolerability of Flurpiridaz F 18 (Flyrcado) have been evaluated across its clinical development program, including Phase 1, 2, and 3 trials involving a substantial number of subjects.

Overview of Adverse Events from Clinical Trials:

Overall, Flurpiridaz F 18 PET imaging procedures have been reported as safe and well-tolerated by patients.8 The safety database for FLYRCADO, as per its prescribing information, includes 1,600 subjects, the majority of whom had known or suspected CAD.4

Common Adverse Reactions:

The most common adverse reactions, defined as those occurring with an incidence of ≥ 2% during FLYRCADO PET MPI performed under rest and stress (either pharmacologic or exercise) conditions, as listed in the FDA prescribing information, include 4:

• Dyspnea (17%)
• Headache (15%)
• Angina pectoris (10%)
• Chest pain (8%)
• Fatigue (7%)
• ST segment changes on ECG (6%)
• Flushing (5%)
• Nausea (4%)
• Abdominal pain (4%)
• Dizziness (4%)
• Arrhythmia (4%)

Less Common Adverse Reactions:

Adverse reactions reported in <2% of subjects who underwent FLYRCADO PET MPI include 4:

• Diarrhea, palpitations, back pain, cardiac conduction disturbances, rash, dysgeusia (altered taste), cough, hypotension, anxiety, vomiting, pruritus (itching), bronchospasm, dry mouth, blood pressure elevation, syncope (fainting), and wheezing.

Warnings, Precautions, and Contraindications:

• Contraindications: There are no listed contraindications for the use of FLYRCADO.[3]
• Warnings and Precautions: The prescribing information highlights several important warnings and precautions:
• Risks Associated with Exercise or Pharmacologic Stress: A significant portion of the potential risks associated with FLYRCADO PET MPI is related to the stress component of the procedure. Patients undergoing either exercise or pharmacologic stress may experience serious adverse cardiovascular or cerebrovascular events, including myocardial infarction, arrhythmias, hypotension, bronchoconstriction, stroke, and seizures. It is mandated that stress testing be performed in a clinical setting where cardiac resuscitation equipment and appropriately trained staff are readily available. If pharmacologic stress is employed, the procedure must adhere to the specific prescribing information for the chosen pharmacologic stress agent.[3]
• Radiation Risks: As with all radiopharmaceuticals, FLYRCADO contributes to the patient's overall long-term cumulative radiation exposure. Such exposure is associated with an increased risk of cancer. Therefore, adherence to safe handling practices is essential to minimize radiation exposure to both patients and healthcare providers. Patients should be advised to ensure adequate hydration before and after the administration of FLYRCADO and to void frequently following the procedure to help reduce radiation dose, particularly to the bladder.[3]
• Use in Pregnancy: There are no available data on the use of Flurpiridaz F 18 in pregnant women. However, all radiopharmaceuticals have the potential to cause fetal harm due to radiation exposure, the extent of which depends on the fetal stage of development and the magnitude of the dose. Additionally, FLYRCADO contains ethanol (a maximum daily dose of 337 mg anhydrous ethanol), and ethanol exposure during pregnancy is associated with potential adverse fetal outcomes. Pregnant patients should be informed of these potential risks.[3]
• Use in Lactation: It is not known whether Flurpiridaz F 18 is excreted in human milk. To minimize potential radiation exposure to a breastfed infant, lactating women should be advised to temporarily discontinue breastfeeding, and to pump and discard breast milk for at least 8 hours following the administration of FLYRCADO.[3]
• Pediatric Use: The safety and effectiveness of FLYRCADO in pediatric patients have not been established.[3]

The safety profile of Flurpiridaz F 18 appears to be largely influenced by the physiological effects of the cardiovascular stress test (whether exercise-induced or pharmacologically induced) rather than by direct toxicity of the radiopharmaceutical itself at diagnostic doses. Many of the commonly reported adverse events, such as dyspnea, angina, chest pain, and ST segment changes [4], are well-recognized manifestations of myocardial ischemia or known side effects of pharmacological stress agents (e.g., adenosine, regadenoson, dipyridamole). The primary warnings detailed in the prescribing information focus predominantly on managing the risks inherent to the stress procedure [3] and on the general principles of radiation safety applicable to all radiopharmaceuticals.[3] The absence of specific contraindications for Flurpiridaz F 18 itself [3] further suggests that the intrinsic toxicity of the agent is low. Consequently, safety management in the clinical use of Flurpiridaz F 18 primarily revolves around careful patient selection for stress testing, appropriate monitoring during and after the stress procedure, and adherence to standard radiation protection protocols.

Table 4: Common Adverse Reactions Reported for Flyrcado (Flurpiridaz F 18) (Incidence ≥ 2%)

Adverse Reaction	Incidence (%)
Dyspnea	17
Headache	15
Angina pectoris	10
Chest pain	8
Fatigue	7
ST segment changes	6
Flushing	5
Nausea	4
Abdominal pain	4
Dizziness	4
Arrhythmia	4

Data sourced from FDA prescribing information.[4] These adverse reactions occurred during FLYRCADO PET MPI under rest and stress (pharmacologic or exercise).

This table provides clinicians with essential information regarding the most frequently observed adverse events, facilitating informed patient counseling and helping to manage expectations prior to the imaging procedure.

9. Dosimetry and Radiation Safety

Understanding the radiation dosimetry associated with Flurpiridaz F 18 (Flyrcado) is crucial for assessing patient risk and ensuring compliance with radiation safety guidelines.

Estimated Radiation Absorbed Doses:

The official FDA prescribing information for FLYRCADO provides detailed estimates of radiation absorbed doses to various organs and tissues, as well as the total body effective dose, resulting from intravenous administration under different imaging protocols (rest, pharmacologic stress using adenosine, and exercise stress).4

Key dosimetry values include:

• Effective Dose:
• For a rest study with 111 MBq (3 mCi) of FLYRCADO, the effective dose is approximately 2.1 mSv.[4]
• For a pharmacologic stress study with 241 MBq (6.5 mCi), the effective dose is approximately 4.6 mSv.[4]
• For an exercise stress study with 352 MBq (9.5 mCi), the effective dose is approximately 5.3 mSv.[4]
• Organ Doses:
• The kidneys were identified as a dose-critical organ in early studies [8], receiving an estimated 0.066 mGy/MBq at rest.
• The heart wall receives an estimated absorbed dose of 0.048 mGy/MBq at rest, 0.09 mGy/MBq during pharmacologic stress, and 0.039 mGy/MBq during exercise stress.[4]
• The urinary bladder wall also receives a notable dose, emphasizing the importance of hydration and frequent voiding.
• Comparison with SPECT: A significant finding from clinical trials (e.g., NCT01347710) is that the radiation exposure associated with a Flurpiridaz F 18 PET MPI study is substantially lower than that from a typical $^{99m}$Tc-SPECT MPI study. For example, one study reported a mean effective dose of approximately 6.1 ± 0.4 mSv for the Flurpiridaz F 18 PET protocol compared to 13.4 ± 3.2 mSv for the SPECT protocol.[11] This represents a more than twofold reduction in radiation burden for the patient.

Radiation Safety Handling and Patient Preparation:

Standard radiation safety protocols must be strictly adhered to when handling and administering FLYRCADO:

• Handling: Healthcare providers should use waterproof gloves and effective radiation shielding (e.g., lead-glass syringe shields) to minimize occupational exposure.[4]
• Qualified Personnel: Radioactive drugs like FLYRCADO should only be used by or under the direct supervision of healthcare providers who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose competence has been approved by the appropriate governmental regulatory agency.[4]
• Patient Preparation: To minimize radiation dose, particularly to the bladder, patients should be instructed to ensure adequate hydration by drinking water before the administration of FLYRCADO and to continue drinking and voiding frequently for several hours after the procedure.[4]

The significantly lower effective radiation dose delivered to patients undergoing Flurpiridaz F 18 PET MPI, when compared to conventional $^{99m}$Tc-SPECT MPI protocols, represents a major clinical advantage.[11] This reduction aligns with the fundamental principle of ALARA (As Low As Reasonably Achievable) in medical imaging, which advocates for minimizing radiation exposure while still obtaining the necessary diagnostic information. This benefit, when considered alongside the documented improvements in diagnostic performance (particularly sensitivity and image quality), makes Flurpiridaz F 18 an attractive alternative from both a clinical efficacy and radiation safety standpoint.

Table 5: Estimated Radiation Absorbed Doses for Flyrcado (Flurpiridaz F 18)

Organ/Tissue	Absorbed Dose per Unit Activity (mGy/MBq) - Rest	Absorbed Dose per Unit Activity (mGy/MBq) - Pharmacologic Stress (Adenosine)	Absorbed Dose per Unit Activity (mGy/MBq) - Exercise Stress
Heart Wall	0.048	0.090	0.039
Kidneys	0.066	0.057	0.027
Liver	0.039	0.044	0.015
Lungs	0.013	0.013	0.009
Red Marrow	0.013	0.013	0.009
Ovaries	0.015	0.014	0.010
Testes	0.010	0.010	0.008
Urinary Bladder Wall	0.043	0.040	0.036
Effective Dose (mSv/MBq)	0.019	0.019	0.015

Adapted from FDA Prescribing Information for FLYRCADO.[4] Doses for other organs are available in the full prescribing information.

This table provides critical dosimetry data essential for radiation safety officers, nuclear medicine physicians, and technologists. It allows for accurate risk assessment, facilitates informed patient counseling regarding radiation exposure, and ensures compliance with radiation safety regulations.

10. Clinical Indications and Prescribing Information

The clinical use of Flyrcado (Flurpiridaz F 18) is guided by its approved indications and specific recommendations for dosage, administration, patient preparation, and imaging protocols as detailed in the official FDA prescribing information.

Approved Indications for Use:

FLYRCADO is a radioactive diagnostic drug indicated for Positron Emission Tomography (PET) myocardial perfusion imaging (MPI). It is intended for use in adult patients with known or suspected coronary artery disease (CAD) to evaluate for myocardial ischemia and infarction. The imaging can be performed under conditions of rest and stress, with stress being induced either pharmacologically or through exercise.1

Recommended Dosage and Administration (Rest/Stress Protocols):

FLYRCADO is administered by intravenous (IV) injection. A typical MPI study involves two separate doses: one for rest imaging and one for stress imaging.1

• 1-Day Rest/Stress Protocol [4]:
• Rest Imaging Dose: 93 MBq to 111 MBq (2.5 mCi to 3 mCi).
• Pharmacologic Stress Imaging Dose: 222 MBq to 241 MBq (6 mCi to 6.5 mCi). The stress dose should be at least 2-fold the rest activity.
• Exercise Stress Imaging Dose: 333 MBq to 352 MBq (9 mCi to 9.5 mCi). The stress dose should be at least 3-fold the rest activity.
• The maximum total volume administered in a single day should not exceed 6.1 mL.
• 2-Day Rest/Stress Protocol [4]:
• For both rest and stress (pharmacologic or exercise) imaging performed on separate days, the recommended activity for each scan is 93 MBq to 111 MBq (2.5 mCi to 3 mCi).
• Administration Technique: FLYRCADO should be administered as an IV bolus injection lasting less than 10 seconds. This should be immediately followed by a flush of 0.9% Sodium Chloride Injection, USP, to ensure complete delivery of the dose.[4]
• Timing Between Doses: When rest and stress imaging are performed on the same day, a minimum time interval between the rest dose and the stress dose administration is required: 30 minutes for pharmacologic stress protocols and 60 minutes for exercise stress protocols.[4]

Patient Preparation and Image Acquisition Protocols:

• Patient Preparation: Patients should be instructed to ensure adequate hydration by drinking water before the administration of FLYRCADO. They should also continue to drink water and void frequently for several hours after the procedure to help minimize radiation exposure, particularly to the bladder.[4]
• Stress Induction:
• Pharmacologic Stress: If pharmacologic stress is used, FLYRCADO should be administered at the time of peak vasodilation, according to the prescribing information for the specific pharmacologic stress agent being used (e.g., adenosine, regadenoson, dipyridamole).[4]
• Exercise Stress: If exercise stress is used, FLYRCADO should be administered after the patient has achieved at least 85% of their age-predicted maximum heart rate or exhibits clear signs or symptoms of ischemia. The patient should then continue to exercise for approximately 1 to 2 minutes following the injection to ensure adequate tracer uptake during stress conditions.[4]
• Image Acquisition [4]:
• Rest Imaging & Pharmacologic Stress Imaging: PET acquisition should begin 5 minutes after the administration of FLYRCADO. Images are typically acquired for 10 minutes using a PET scanner in 3D mode. For pharmacologic stress studies, dynamic imaging may optionally be performed, starting immediately prior to the FLYRCADO injection.
• Exercise Stress Imaging: Image acquisition should begin approximately 15 to 25 minutes after FLYRCADO administration, once the patient has been positioned on the scanner and their respiration has started to return to normal. Images are acquired for 10 minutes, typically in 3D mode.
• Image Reconstruction: For both rest and stress imaging, image reconstruction must include appropriate attenuation correction to ensure quantitative accuracy.

Drug Interactions:

The official FDA prescribing information for FLYRCADO 4 does not specifically list drug interactions. Other sources like RxList and Medscape state that no moderate or minor interactions have been noted but advise patients and clinicians to check with a healthcare professional regarding all medications being taken.35 Patient education materials also typically advise patients to inform their doctors about all medications they are currently using.36

The absence of dedicated drug interaction studies or specific interaction warnings in the provided prescribing information represents a potential data gap. While no major interactions are currently flagged, the theoretical potential for interactions, for example, with drugs that significantly affect mitochondrial function (given Flurpiridaz F 18's binding to MC-1) or those that markedly alter cardiac physiology or blood flow, cannot be entirely dismissed without specific investigation. This area may warrant ongoing clinical vigilance or further research, especially as the agent sees broader clinical use in patients who are often on multiple concomitant medications for cardiovascular and other conditions.

Table 6: Recommended Dosage and Administration for Flyrcado (Flurpiridaz F 18)

Protocol Type	Imaging Stage	Recommended Activity (MBq)	Recommended Activity (mCi)	Minimum Interval Between Doses (Same Day)	Key Administration Notes
1-Day Rest/Pharmacologic Stress	Rest	93 - 111	2.5 - 3	N/A	IV Bolus <10s, followed by 0.9% NaCl flush.
	Pharmacologic Stress	222 - 241	6 - 6.5	30 minutes	Stress dose $\ge$2x rest dose. Max 1-day volume 6.1 mL.
1-Day Rest/Exercise Stress	Rest	93 - 111	2.5 - 3	N/A	IV Bolus <10s, followed by 0.9% NaCl flush.
	Exercise Stress	333 - 352	9 - 9.5	60 minutes	Stress dose $\ge$3x rest dose. Max 1-day volume 6.1 mL.
2-Day Protocol (Rest & Stress on separate days)	Rest	93 - 111	2.5 - 3	N/A	IV Bolus <10s, followed by 0.9% NaCl flush.
	Stress (Pharm or Ex)	93 - 111	2.5 - 3	N/A (Separate days)	IV Bolus <10s, followed by 0.9% NaCl flush.

Data adapted from FDA Prescribing Information for FLYRCADO.[4]

This table provides essential, standardized guidelines for the dosing and administration of Flyrcado across different clinical protocols. Adherence to these recommendations is critical for ensuring procedural consistency, optimizing image quality, and maintaining radiation safety.

11. Discussion and Future Perspectives

Flurpiridaz F 18 (Flyrcado) represents a significant development in the field of non-invasive cardiac imaging, offering several advantages over existing modalities for the assessment of coronary artery disease.

Clinical Impact and Advantages over Existing Modalities:

The clinical trial program for Flurpiridaz F 18 has consistently demonstrated its superior diagnostic sensitivity for CAD detection when compared directly to $^{99m}$Tc-SPECT MPI. This enhanced sensitivity is particularly evident in patient populations that are traditionally challenging to image with SPECT, such as women and obese individuals, due to attenuation artifacts.11 Beyond sensitivity, Flurpiridaz F 18 PET also provides better overall image quality and allows for greater diagnostic certainty by interpreters.3

A crucial advantage from a patient safety perspective is the significantly lower radiation exposure associated with Flurpiridaz F 18 PET protocols compared to standard $^{99m}$Tc-SPECT MPI.[11] This reduction in radiation burden is an important consideration, especially for patients who may require multiple imaging studies over time.

The use of the fluorine-18 radioisotope, with its ~110-minute half-life, confers substantial logistical benefits. It allows for centralized production in regional cyclotron facilities and distribution as unit doses. This model improves the accessibility of PET MPI to a wider range of hospitals and imaging centers, including those without on-site cyclotrons or generators. Furthermore, this half-life makes exercise stress testing, a more physiological stressor for many patients, readily feasible, as there is ample time between tracer injection at peak exercise and the subsequent imaging window.[1]

Moreover, Flurpiridaz F 18 PET holds the potential for accurate quantitative assessment of myocardial blood flow (MBF) and myocardial flow reserve (MFR).[9] Quantitative perfusion data can offer incremental diagnostic and prognostic information beyond relative perfusion assessment, potentially improving risk stratification and guiding therapeutic decisions more effectively.[41]

Potential for Broader Clinical Adoption:

The confluence of improved diagnostic accuracy, significant logistical advantages, and a lower patient radiation dose positions Flurpiridaz F 18 to potentially drive a broader clinical adoption of cardiac PET MPI.12 It may become the preferred non-invasive imaging agent for patients who are difficult to image with SPECT or in clinical scenarios where high diagnostic certainty and quantitative data are paramount.3 Preliminary economic modeling suggests that while the introduction of F18-PET-MPI with Flurpiridaz might involve a nominal increase in initial procedural costs, there is potential for overall cost-savings due to improved diagnostic accuracy leading to a reduction in downstream adverse cardiac outcomes (like myocardial infarction and cardiac mortality) and fewer unnecessary invasive coronary angiographies.41

Unanswered Questions and Future Research Directions:

Despite the promising data and recent FDA approval, several areas warrant further investigation:

• The added clinical value of quantitative MBF and MFR measurements obtained with Flurpiridaz F 18 PET, particularly in comparison to existing PET tracers capable of quantification, needs to be more definitively established in diverse patient populations and clinical scenarios.[17]
• Long-term outcome studies are needed to fully understand the impact of Flurpiridaz F 18 PET-guided management on patient prognosis and overall healthcare costs.
• The utility of Flurpiridaz F 18 in assessing other cardiac conditions beyond obstructive CAD, such as coronary microvascular dysfunction, warrants exploration, as suggested by its favorable extraction characteristics.[13]
• Further refinement of interpretive criteria, especially concerning specificity in relation to varying degrees of CAD severity and patient pre-test probabilities, may be beneficial to optimize its diagnostic performance across the full spectrum of patients.[13]
• Dedicated drug interaction studies would provide a more complete understanding of its safety profile in patients on multiple medications.

Flurpiridaz F 18 has the potential to be more than just an incremental improvement in myocardial perfusion imaging; it could represent a significant step towards making high-accuracy PET MPI a more dominant non-invasive modality for CAD assessment. The current landscape of MPI involves a trade-off between the wider accessibility but generally lower accuracy of SPECT, and the higher accuracy but more limited accessibility of traditional PET. Flurpiridaz F 18 aims to bridge this gap by offering PET-level diagnostic performance with substantially improved logistical feasibility.[12] Its documented superiority over SPECT in key metrics like sensitivity and image quality, especially in challenging patient cohorts [11], is compelling. If the economic and practical aspects of its implementation are managed effectively, these advantages could drive a considerable shift from SPECT towards Flurpiridaz F 18 PET for a larger proportion of MPI studies.

While qualitative (visual) interpretation of Flurpiridaz F 18 PET images already demonstrates significant benefits, the true, transformative potential of this tracer may lie in its capacity to provide robust and accurate quantitative measures of myocardial blood flow and flow reserve. The favorable pharmacokinetic properties of Flurpiridaz F 18, particularly its high and flow-independent extraction fraction [3], combined with the inherent quantitative capabilities of PET technology, make it exceptionally well-suited for such measurements. Quantitative perfusion data can overcome limitations of relative (qualitative) imaging, such as in the detection of balanced, multivessel ischemia or diffuse coronary atherosclerosis, and can provide more precise risk stratification.[13] The full clinical impact of Flurpiridaz F 18 will likely be realized when quantitative flow analysis becomes a routine component of its clinical application, moving MPI beyond simple defect detection towards a more comprehensive physiological assessment of coronary circulatory health and myocardial viability. Future research and clinical adoption should focus on standardizing and leveraging this quantitative capability to maximize its diagnostic and prognostic power.

12. Conclusions

18F-BMS-747158-02, approved as Flurpiridaz F 18 (Flyrcado), is a novel positron emission tomography myocardial perfusion imaging agent that has demonstrated significant advancements over existing non-invasive cardiac imaging modalities. Its mechanism of action, involving high-affinity binding to mitochondrial complex I, coupled with the favorable physical characteristics of the fluorine-18 label, results in high-quality images, excellent myocardial extraction, and prolonged retention.

Preclinical studies robustly supported its translation to human trials, where extensive Phase 1, 2, and 3 investigations have established its safety and diagnostic efficacy. Notably, pivotal Phase 3 trials (NCT01347710 and NCT03354273) have shown that Flurpiridaz F 18 PET offers superior sensitivity for the detection of coronary artery disease compared to traditional $^{99m}$Tc-SPECT MPI, with non-inferior specificity demonstrated in the more recent trial. This enhanced diagnostic performance is particularly evident in challenging patient populations, such as women and obese individuals. Furthermore, Flurpiridaz F 18 PET MPI is associated with a significantly lower radiation burden for the patient than SPECT.

The ~110-minute half-life of fluorine-18 provides crucial logistical advantages, enabling centralized production, unit-dose distribution, and the practical implementation of exercise stress protocols. These factors are poised to increase the accessibility and utility of advanced cardiac PET imaging. While its safety profile is generally benign, with most adverse events related to the stress procedure itself, continued pharmacovigilance is standard. The potential for quantitative myocardial blood flow and flow reserve measurements with Flurpiridaz F 18 represents a key area for future development and clinical integration, promising a more comprehensive assessment of coronary physiology.

In summary, Flurpiridaz F 18 (Flyrcado) stands as a clinically validated and FDA-approved PET radiopharmaceutical that offers improved diagnostic accuracy, enhanced logistical feasibility, and reduced radiation exposure compared to older MPI techniques. Its introduction marks a significant step forward in non-invasive cardiac imaging, with the potential to refine diagnostic pathways for coronary artery disease and improve patient care.

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