Cardiac imaging and uptake mechanism of 18F LMI1195, a novel PET cardiac neuronal imaging agent

Objectives Imaging with 123I-meta-iodobenzylguanidine (MIBG) was shown to predict heart failure progression, but the image quality is poor. Like MIBG, LMI1195 is designed as a substrate for norepinephrine transporter (NET), but labeled with 18F to take advantages of PET technology. This study evaluated cardiac image quality of LMI1195 and its affinity and selectivity to NET and uptake kinetics, in comparison with norepinephrine (NE).

Methods The affinity (Ki) was determined in a competition binding assay by incubating 19F-LMI1195, a cold analog of LMI1195, or NE with 3H-desmethylimipramine in cell membrane overexpressing human NET. The uptake selectivity was assessed by measuring LMI1195 or 3H-NE cell uptake with and without pretreatment of desipramine, a selective NET inhibitor, in SK-N-SH (human neuroblastoma) and PC-12 (rat pheochromocytoma) cells. In SK-N-SH cells, the uptake kinetics (Km and Vmax) was evaluated by measuring NET mediated uptake of 19F-LMI1195 or NE at various concentrations. LMI1195 cardiac image quality was evaluated by PET imaging (~1.5 mCi, i.v.) in rabbits in the presence and absence of desipramine (1 mg/kg).

Results In competition binding assays, Ki values for LMI1195 and NE were similar (5.2±1.1 and 3.4±1.3µM). In cell studies, blockade of NET inhibited LMI1195 and NE uptake by 66±7 and 93±1% in PC-12 cells, and 91±1 and 97±1% in SK-N-SH cells. In SK-N-SH cells, Km and Vmax values for LMI1195 were 1.4±0.3 µM and 6.0±1.3pMol/million cells/min similar to that of NE (2.0±0.4µM and 6.2±0.7pMol/million cells/min). Moreover, LMI1195 cell uptake was inhibited by 19F-LMI1195 or NE in a concentration-dependent manner. Imaging in rabbits with LMI1195 showed clear myocardium uptake with low liver activity. Cardiac uptake could be inhibited by desipramine.

Conclusions The cell uptake profile of LMI1195 is similar to NE with high selectivity. Cardiac images of LMI1195 are clear and the heart uptake is mediated by NET