Biodistribution and Radiation Dosimetry of LMI1195: First-in-Human Study of a Novel ¹⁸F-Labeled Tracer for Imaging Myocardial Innervation

Abstract

A novel 18 F-labeled ligand for the norepinephrine transporter (N-[3-bromo-4-(3-18 F-fluoro-propoxy)-benzyl]-guanidine [LMI1195]) is in clinical development for mapping cardiac nerve terminals in vivo using PET. Human safety, whole-organ biodistribution, and radiation dosimetry of LMI1195 were evaluated in a phase 1 clinical trial. Methods: Twelve healthy subjects at 3 clinical sites were injected intravenously with 150-250 MBq of LMI1195. Dynamic PET images were obtained over the heart for 10 min, followed by sequential whole-body images for approximately 5 h. Blood samples were obtained, and heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. Residence times were determined from multiexponential regression of organ region-ofinterest data normalized by administered activity (AA). Radiation dose estimates were calculated using OLINDA/EXM. Myocardial, lung, liver, and blood-pool standardized uptake values were determined at different time intervals. Results: No adverse events due to LMI1195 were seen. Blood radioactivity cleared quickly, whereas myocardial uptake remained stable and uniform throughout the heart over 4 h. Liver and lung activity cleared relatively rapidly, providing favorable target-to-background ratios for cardiac imaging. The urinary bladder demonstrated the largest peak uptake (18.3% AA), followed by the liver (15.5% AA). The mean effective dose was 0.026 ± 0.0012 mSv/MBq. Approximately 1.6% AA was seen in the myocardium initially, remaining above 1.5% AA (decay-corrected) through 4 h after injection. The myocardium-to-liver ratio was approximately unity initially, increasing to more than 2 at 4 h. Conclusion: These preliminary data suggest that LMI1195 is well tolerated and yields a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. The kinetics of myocardial and adjacent organ activity suggest that cardiac imaging should be possible with acceptable patient radiation dose.

Retention Kinetics of the 18F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with 11C-Hydroxyephedrine and 123I-MIBG

“…Desipramine added into the perfusion buffer markedly reduced the extraction to 4% at 4 mL/min/g. Furthermore, in vivo PET studies have confirmed the high contrast of 18 F-LMI1195 cardiac uptake in rabbits, monkeys, and humans (4,5). Notably, the specific neural transport observed in these species is not the same as seen in small rodents (16,17).…”

“…Furthermore, minimal liver uptake in comparison to other conventional nerve tracers was suggested in the animal experiments and is preferable for assessment of the left ventricular inferior wall. Most recently, a human volunteer study (clinical phase I trial) with 18 F-LMI1195 demonstrated promising clinical results, with uniform myocardial tracer uptake in the left ventricular wall and acceptable radiation exposure (5). Further mechanistic details of 18 F-LMI1195 cardiac retention are not yet fully elucidated.…”

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

“…The results of imaging studies in rats, rabbits and non-human primates suggested that [ 18 F]FPOBBG (LMI1195) was a promising agent for PET imaging of cardiac sympathetic neuronal function [31] and a phase I clinical evaluation of this agent has been reported recently [37]. Although our evaluation [ 18 F]FPOIBG indicated it be not up to the par with MIBG (see below), we wondered whether its biological properties will be comparable to that of [ 18 F]FPOBBG.…”

Application of Cardiac Neurohormonal Imaging to Heart Failure, Transplantation, and Diabetes

“…Nevertheless, the need for a nearby cyclotron makes 11 C-HED impractical for most practitioners. 18 F compounds that are more practical (e.g., 18 F-LMI-1195 (flurobenzylguanidine)) are under investigation [68].…”