Evaluation of LMI1195, a Novel ¹⁸ F-Labeled Cardiac Neuronal PET Imaging Agent, in Cells and Animal Models

Abstract

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.)

Assessment of the 18F-Labeled PET Tracer LMI1195 for Imaging Norepinephrine Handling in Rat Hearts

“…Synthesis and quality control of 18 F-LMI1195 were performed using a previously described procedure (10). 18 F-LMI1195, with a radiochemical purity of 98% or more and specific activity of 600 GBq/ mmol or more, was used in the biologic evaluation and small-animal PET studies.…”

“…Initial characterization of this new compound has been reported by Yu et al (10). High human norepinephrine transporter binding affinity was proven by experiments using cell membranes overexpressing human norepinephrine transporter and human neuroblastoma cells (10). Furthermore, by performing in vivo norepinephrine neural uptake-1 blocking experiments with desipramine in New Zealand White rabbits and nonhuman primates, resulting in significant cardiac tracer uptake reduction, a high selectivity for norepinephrine transporters was proven.…”

Assessing the activity of cardiac sympathetic innervation with a novel PET tracer

“…LMI1195 (N-[3-bromo-4-(3-[ 18 F]fluoro-propoxy)-benzyl]-guanidine) was designed as a benzylguanidine analogue to act as substrate for the noradrenaline transporter incorporating 18 F to achieve a longer half-life for PET imaging. The authors have demonstrated in a previous O. Rimoldi IBFM CNR Milan, Vita-Salute University, Milan, Italy paper the similarity of the kinetics to those of noradrenaline [11], and in this paper they compared the cellular uptake of 3 H-noradrenaline and 123 I-MIBG in vitro in human neuroblastoma cells expressing noradrenaline. The uptake of LMI1195 was higher than that of 3 H-noradrenaline and slightly lower than that of 123 I-MIBG with a broader variance, suggesting that LMI1195, noradrenaline and MIBG share the same transporter mechanism.…”

“…The paper by Yu et al in this issue of EJNMMI [10], describes a cardiac neuronal imaging agent, LMI1195, recently developed by a company manufacturing diagnostic imaging agents [11]. LMI1195 (N-[3-bromo-4-(3-[ 18 F]fluoro-propoxy)-benzyl]-guanidine) was designed as a benzylguanidine analogue to act as substrate for the noradrenaline transporter incorporating 18 F to achieve a longer half-life for PET imaging.…”

“…A low uptake of the tracer in a definite region can have a binary interpretation: on the one hand it might indicate a lower density of neural terminals which have been damaged, and on the other hand sympathetic overactivity may increase the amount of endogenous mediator in the synaptic cleft which displaces the radiotracer. The latter phenomenon has been quantified using 11 C-HED and is distinctive of arrhythmogenic cardiomyopathies [6,7].…”