Roles of cardiac norepinephrine uptake 1 and 2 in evaluation of LMI1195, a new cardiac PET neuronal imaging agent, in rats, rabbits and nonhuman primates

Objectives Norepinephrine (NE) released in the heart is mainly cleared by neuronal uptake 1 (NE transporter) in rabbits, nonhuman primates (NHP) and humans, and by uptake 1 and 2 in rats. LMI1195, like NE and 123I- meta-iodobenzylguanidine (MIBG), is a substrate for uptake 1 and labeled with 18F. This study examined species differences associated with cardiac uptake 1 and 2 for LMI1195 heart uptake.

Methods Desipramine (mg/kg), a selective uptake 1 inhibitor, was used to block cardiac uptake 1 in rats (10, ip), rabbits (1, iv) and NHPs (0.5, iv). 6-hydroxydopamine (mg/kg), a neurotoxin, was injected to induce sympathetic denervation in rats (100, ip) and rabbits (25, iv for 4 days). LMI1195 or MIBG heart uptake was assessed by tissue sampling at 60 minutes post injection. LMI1195 imaging was also performed.

Results In rats, uptake 1 blockade did not alter LMI1195 heart uptake compared to the control [1.41±0.07 vs. 1.47±0.22 % injected dose per gram tissue (%ID/g)]. In contrast, LMI1195 heart uptake was reduced by 68% in uptake 1 blocked rabbits. In sympathetic denervated rats, LMI1195 heart uptake was similar to the control (2.18±0.39 vs. 2.58±0.76 %ID/g). However, the uptake decreased markedly (79%) in denervated rabbits. Similar results were found in MIBG heart uptake in rats and rabbits with uptake 1 blockade or sympathetic denervation. Consistently, LMI1195 cardiac imaging showed comparable myocardial activity in sympathetic denervated rats to the control, but marked activity reduction in denervated rabbits and uptake 1 blocked rabbits and NHPs.

Conclusions In rabbits and NHPs with uptake 1 as the main cardiac NE transporter, similar to humans, LMI1195 shows high selectivity to neuronal uptake 1 and can be used in evaluation of cardiac sympathetic denervation. However, due to the high cardiac uptake 2 expression, evaluation of uptake 1 substrate based neuronal imaging agents in rats should be used cautiously