A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood pool into the myocardium (0.48-0.62% ID/g), lung (0.63-0.97% ID/g), and liver (1.03-1.14% ID/g). Dynamic μPET imaging confirmed the in vivo dissection studies.

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-[3-Bromo-4-(3-[F]fluoro-propoxy)-benzyl]-guanidine (LMI1195) is a newly developed 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 I-metaiodobenzylguanidine (MIBG) in vivo. The affinity (Ki) of LMI1195 for NET was 5.16 2.83 mol/L, similar to that of NE (3.36 2.77 mol/L) in a cell membrane–binding assay. Similarly, LMI1195 uptake kinetics examined in a human neuroblastoma cell line had Km and Vmax values of 1.44 0.76 mol/L and 6.05 3.09 pmol/million cells per minute, comparable to NE (2.01 0.85 mol/L and 6.23 1.52 pmol/million cells per minute). In rats, LMI1195 heart uptake at 15 and 60 minutes after intravenous administration was 2.36 0.38% and 2.16 0.38% injected dose per gram of tissue (%ID/g), similar to I-MIBG (2.14 0.30 and 2.19 0.27%ID/g). However, the heart to liver and lung uptake ratios were significantly higher for LMI1195 than for I-MIBG. In rabbits, desipramine (1 mg/kg), a selective NET inhibitor, blocked LMI1195 heart uptake by 82%, which was more effective than 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 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.)

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 -[3-Bromo-4-(3-[ 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-meta-iodobenzylguanidine (MIBG) in vivo. The affinity (K i ) of LMI1195 for NET was 5.16±2.83 μmol/L, similar to that of NE (3.36±2.77 μmol/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 1.44±0.76 μmol/L and 6.05±3.09 pmol/million cells per minute, comparable to NE (2.01±0.85 μmol/L and 6.23±1.52 pmol/million cells per minute). In rats, LMI1195 heart uptake at 15 and 60 minutes after intravenous administration was 2.36±0.38% and 2.16±0.38% injected dose per gram of tissue (%ID/g), similar to 123 I-MIBG (2.14±0.30 and 2.19±0.27%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.

BMS747158-02 is an 18F-labeled agent being developed for PET myocardial perfusion imaging. This study examined impacts of feeding state and anesthetic on cardiac imaging and uptake of this agent in rats in comparison with 18F-fluorodeoxyglucose (FDG).