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 microg/kg. However, marked alterations in cardiorespiratory parameters were observed after injection of N-methyl-NFEP (0.5 microg/kg, IV) to an awake dog. Our results suggest that although the binding characteristics of [18F]NFEP and [18F]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.
Ding
Y S
YS
Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. ding@bnl.gov
Molina
P E
PE
Fowler
J S
JS
Logan
J
J
Volkow
N D
ND
Kuhar
M J
MJ
Carroll
F I
FI
D000818:Animals; D001549:Benzamides; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D005260:Female; D005462:Fluorine Radioisotopes; D009538:Nicotine / Q000494:pharmacology; D010215:Papio; D011725:Pyridines / Q000493:pharmacokinetics* / Q000633:toxicity; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014055:Tomography, Emission-Computed
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005462:Fluorine Radioisotopes; C120326:N-methylnorchlorofluoroepibatidine; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C115362:fluoronorchloroepibatidine; D009538:Nicotine