Synthesis of a fluorine-18 labeled derivative of epibatidine for in vivo nicotinic acetylcholine receptor PET imaging

Epibatidine (exo-2-(2'-chloro-5'-pyridyl)-7-azabicyclo[2.2.1]heptane), a na tural compound isolated from the skin of the Ecuadorian poison frog Epipedo bates tricolor, is the most potent nicotinic acetylcholine receptor (nAChR) agonist reported to date. In order to visualize and quantify in vivo these receptors in human brain using Positron Emission Tomography (PET), [F-18]n orchlorofluoroepibatidine (exo-2-(2'-[F-18]fluoro-5'-pyridyl)-7-azabicyclo[ 2.2.1]heptane), a fluorine-18 (t(1/2): 110 min) radiolabeled derivative of epibatidine has been designed. The corresponding 2'-bromo-, 2'-iodo- and 2' -nitro exo-2-(5'-pyridyl)-7-azabicyclo[2.2.1]heptane analogues as labeling precursors, as well as norchlorofluoroepibatidine as a reference compound h ave been synthesized by reductive, stereoselective, palladium-catalyzed Hec k-type coupling between an N-Boc protected azanorbornene and the correspond ing halopyridine. [F-18]Norchlorofluoroepibatidine has been radiolabeled wi th fluorine-18 by nucleophilic aromatic substitution from the corresponding Boc-protected halo- and nitro precursors using [F-18]FK-K-222 complex in D MSO by conventional heating (at 150-180 degrees C for 10 min) or microwave activations (at 100 Watt, for 1 to 2.5 min), followed by TFA-removal of the protective group. Typically, using the microwave activation procedure, 60- 80 mCi (2.22-2.96 GBq) of pure [F-18]norchlorofluoroepibatidine could be ob tained in less than 2 h (110-115 min) from the bromo labeling precursor, wi th specific radioactivities of 1.5-2.5 Ci/mu mol (55.5-92.5 GBq/mu mol) cal culated for End of Bombardment. The preliminary PET experiments in baboon ( Papio papio) with [F-18]norchlorofluoroepibatidine show a high uptake and a rapid accumulation of the radiotracer into the brain within 30 min. In the thalamus, a nAChR rich area, uptake of radioactivity reached a maximum at 40 min (10% I.D./100 mt tissue). The ratio of radioactivity thalamus/cerebe llum (the latter being a nAChR poor area) was 2 at 40 min and increased wit h time, up to 4.3 at 160 min. Its specific regiodistribution and its high r atio of specific-to-nonspecific binding confirm the ideal profile of [F-18] norchlorofluoroepibatidine as a suitable radioligand for PET imaging of nAC hRs in the brain. (C) 1999 Elsevier Science Ltd. All rights reserved.