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-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.)

A series of fluorinated pyridazinone derivatives with IC50 values ranging from 8 to 4000 nM for the mitochondrial complex 1 (MC1) have been prepared. Structure-activity relationship (SAR) assessment indicated preference of the fluorine label to be incorporated on an alkyl side chain rather than directly on the pyridazinone moiety. Tissue distribution studies of a series of analogues ([18F] 22-28) in Sprague-Dawley (SD) rats identified [18F]27 as the most promising radiotracer with high uptake in cardiac tissue (3.41%ID/g; 30 min post injection) in addition to favorable heart to nontarget organ distribution ratios. MicroPET images of SD rats and nonhuman primates after [18F]27 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.