Comparative studies of epibatidine derivatives [18F]NFEP and [18F]N-methyl-NFEP:: Kinetics, nicotine effect, and toxicity

We have previously shown that [F-18]norchlorofluoroepibatidine ([F-18]NFEP) would be an ideal radiotracer for positron emission tomography (PET) imaging of nicotinic acetylcholine receptors (nAChR); however, its high toxicity is a limiting factor for human studies. We, therefore, synthesized its N-methyl derivative ([F-18]N-Me-NFEP) and carried out comparative studies. The distribution volumes for different brain regions were higher for [F-18]N-Me-NFEP than those for [F-18]NFEP (average: 52.5 +/- 0.9 vs. 36.4 +/- 0.7 for thalamus), though the distribution volume (DV) ratios were similar (3.93 +/- 0.27 vs. 3.65 +/- 0.19 for thalamus to cerebellum). Treatment with nicotine reduced the binding of both radiotracers. Toxicology studies in awake rats showed that N-methyl-NFEP has a lower mortality (0 vs. 30%) and smaller effect on plasma catecholamines than NFEP at a dose of 1.5 mu g/kg, However, marked alterations in cardiorespiratory parameters were observed after injection of N-methyl-NFEP (0.5 mu g/kg, IV) to an awake dog, Our results suggest that although the binding characteristics of [F-18]NFEP and [F-18]N-Me-NFEP appear to be ideally suited for PET imaging studies of the human brain, their relatively small safety margin will limit their use in humans. NUCL MED BIOL 26;1:139-148, 1999. (C) 1999 Elsevier Science Inc.