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

We have previously shown that [¹⁸F]norchlorofluoroepibatidine ([¹⁸F]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 ([¹⁸F]N-Me-NFEP) and carried out comparative studies. The distribution volumes for different brain regions were higher for [¹⁸F]N-Me-NFEP than those for [¹⁸F]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 μg/kg. However, marked alterations in cardiorespiratory parameters were observed after injection of N-methyl-NFEP (0.5 μg/kg, IV) to an awake dog. Our results suggest that although the binding characteristics of [¹⁸ F]NFEP and [¹⁸ F]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.