PET allows for quantitative, regional myocardial perfusion imaging. The short half-lives of the perfusion tracers currently in use limit their clinical applicability. Here, the biodistribution and imaging quality of a new 18 F-labeled myocardial perfusion agent ( 18 F-BMS-747158-02) in an animal model are described. Methods: The biodistribution of 18 F-BMS-747158-02 was determined at 10 and 60 min after injection. The first-pass extraction fraction of the tracer was measured in isolated rat hearts perfused with the Langendorff method. Small-animal PET imaging was used to study tracer retention. Results: The biodistribution at 10 min after injection demonstrated high myocardial uptake (3.1 percentage injected dose per gram [%ID/g]) accompanied by little activity in the lungs (0.3 %ID/g) and liver (1.0 %ID/g). The tracer showed a high and flow-independent myocardial first-pass extraction fraction, averaging 0.94 (SD 5 0.04). PET imaging provided excellent delineation of myocardial structures. The heartto-lung activity ratio increased from 4.7 to 10.2 between 1 and 15 min after tracer injection (at rest). Adenosine infusion (140 mg/ kg/min) led to a significant increase in myocardial tracer retention (from 1.68 [SD 5 0.23]) s 21 to 3.21 [SD 5 0.92] s 21 ; P 5 0.03). Conclusion: The observation of a high and flow-independent first-pass extraction fraction promises linearity between tracer uptake and myocardial blood flow. Sustained myocardial tracer uptake, combined with high image contrast, will allow for imaging protocols with tracer injection at peak exercise followed by delayed imaging. Thus, 18 F-BMS-747158-02 is a promising new tracer for the quantitative imaging of myocardial perfusion and can be distributed to imaging laboratories without a cyclotron.
BMS-747158-02 exhibited high and sustained cardiac uptake that was proportional to blood flow, and it represents a new class of PET myocardial perfusion imaging agent.
F-18 BMS-747158-02 is a novel positron emission tomography cardiac tracer targeting MC-I in cardiomyocytes with rapid uptake and slow washout. These characteristics allow fast and sustained accumulation in the heart.
Background— Positron-emission tomography (PET) tracers for myocardial perfusion are commonly labeled with short-lived isotopes that limit their widespread clinical use. 18 F-BMS-747158-02 ( 18 F-BMS) is a novel pyridaben derivative that was evaluated for assessment of myocardial perfusion by comparison with 13 N-ammonia ( 13 NH 3 ) and with radioactive microspheres in a pig model. Methods and Results— Fourteen pigs injected with 500 MBq of 13 NH 3 or 100 to 200 MBq of 18 F-BMS underwent dynamic PET at rest and during pharmacological stress. In 8 of these pigs, 18 F-BMS was injected during stress combined with transient, 2.5-minute constriction of the left anterior descending coronary artery. Radioactive microspheres were coinjected with 18 F-BMS. Ratios of myocardial tracer uptake to surrounding tissues were determined, and myocardial blood flow was quantified by compartmental modeling. Both tracers showed high and homogeneous myocardial uptake. Compared with 13 NH 3 , 18 F-BMS showed higher activity ratios between myocardium and blood (rest 2.5 versus 4.1; stress 2.1 versus 5.8), liver (rest 1.2 versus 1.8; stress 0.7 versus 2.0), and lungs (rest 2.5 versus 4.2; stress 2.9 versus 6.4). Regional myocardial blood flow assessed with 18 F-BMS PET showed good correlation ( r =0.88, slope=0.84) and agreement (mean difference −0.10 [25th percentile −0.3, 75th percentile 0.1 mL · min −1 · g −1 ]) with that measured with radioactive microspheres over a flow range from 0.1 to 3.0 mL · min −1 · g −1 . The extent of defects induced by left anterior descending coronary artery constriction measured by 18 F-BMS and microspheres also correlated closely ( r =0.63, slope=1.1). Conclusions— 18 F-BMS-747158-02 is a very attractive new PET perfusion tracer that allows quantitative assessment of regional myocardial perfusion over a wide flow range. The long half-life of 18 F renders this tracer useful for clinical PET/CT applications in the workup of patients with suspected or proven coronary artery disease.
Background-Heart failure has been associated with impaired cardiac sympathetic neuronal function. Cardiac imaging with radiolabeled agents that are substrates for the neuronal norepinephrine transporter (NET) has demonstrated the potential to identify individuals at risk of cardiac events. N- 18 F]fluoro-propoxy)-benzyl]-guanidine (LMI1195) is a newly developed 18 F-labeled NET substrate designed to allow cardiac neuronal imaging with the high sensitivity, resolution, and quantification afforded by positron emission tomography (PET). Methods and Results-LMI1195 was evaluated in comparison with norepinephrine (NE) in vitro and 123 I-metaiodobenzylguanidine (MIBG) in vivo. The affinity (K i ) of LMI1195 for NET was 5.16Ϯ2.83 mol/L, similar to that of NE (3.36Ϯ2.77 mol/L) in a cell membrane-binding assay. Similarly, LMI1195 uptake kinetics examined in a human neuroblastoma cell line had K m and V max values of 1.44Ϯ0.76 mol/L and 6.05Ϯ3.09 pmol/million cells per minute, comparable to NE (2.01Ϯ0.85 mol/L and 6.23Ϯ1.52 pmol/million cells per minute). In rats, LMI1195 heart uptake at 15 and 60 minutes after intravenous administration was 2.36Ϯ0.38% and 2.16Ϯ0.38% injected dose per gram of tissue (%ID/g), similar to 123 I-MIBG (2.14Ϯ0.30 and 2.19Ϯ0.27%ID/g). However, the heart to liver and lung uptake ratios were significantly higher for LMI1195 than for 123 I-MIBG. In rabbits, desipramine (1 mg/kg), a selective NET inhibitor, blocked LMI1195 heart uptake by 82%, which was more effective than 123 I-MIBG (53%), at 1 hour after dosing. Sympathetic denervation with 6-hydroxydopamine, a neurotoxin, resulted in a marked (79%) decrease in LMI1195 heart uptake. Cardiac PET imaging with LMI1195 in rats, rabbits, and nonhuman primates revealed clear myocardium with low radioactivity levels in the blood, lung, and liver. Imaging in rabbits pretreated with desipramine showed reduced heart radioactivity levels in a dose-dependent manner. Additionally, imaging in sympathetically denervated rabbits resulted in low cardiac image intensity with LMI1195 but normal perfusion images with flurpiridaz F 18, a PET myocardial perfusion imaging agent. In nonhuman primates pretreated with desipramine (0.5 mg/kg), imaging with LMI1195 showed a 66% decrease in myocardial uptake. In a rat model of heart failure, the LMI1195 cardiac uptake decreased as heart failure progressed. Conclusions-LMI1195 is a novel 18 F imaging agent retained in the heart through the NET and allowing evaluation of the cardiac sympathetic neuronal function by PET imaging. (Circ Cardiovasc Imaging. 2011;4:435-443.)
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