Synthesis and evaluation of N-[11C]methylated analogues of epibatidine as tracers for positron emission tomographic studies of nicotinic acetylcholine receptors.
Four halogen-substituted analogues of N-methylepibatidine, a nicotinic acetylcholine receptor (nAChR) ligand, were synthesized. They were (+/-)-exo-N-methyl-2-(2-halogeno-5-pyridyl)-7-azabicyclo[2. 2.1]heptanes, where halogeno = F (1a), Cl (2a), Br (3a), I (4a). (+/-)-N-Ethylepibatidine (2b) also was synthesized. The compounds 1a, 2a, 3a, and 4a and their corresponding normethyl analogues 1, 2, 3, and 4 inhibited the in vitro binding of [3H]epibatidine to nAChRs to a similar degree, with affinities in the 27-50 pM range. The binding affinity of N-ethylepibatidine (2b), however, was substantially lower. The N-[11C]methyl derivatives of 1, 2, and 3 were synthesized from high-specific radioactivity [11C]methyl iodide using a high-temperature/high-pressure technique. The corresponding radiolabeled compounds [11C]1a, [11C]2a, and [11C]3a were administrated to mice intravenously. The pattern of regional distribution of the three tracers in the mouse brain following intravenous administration matched those of [3H]epibatidine, [3H]norchloroepibatidine, and (+/-)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), which are highly specific nAChR probes. The initial brain uptake of the 11C analogues and the acute toxicity of the corresponding authentic nonlabeled compounds appeared to be related to their lipophilicity.
Brain Imaging Center, Intramural Research Program, National Institute on Drug Abuse, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA.ahorti@intra.nida.nih.gov
A G
AG
Horti
U
U
Scheffel
A S
AS
Kimes
J L
JL
Musachio
H T
HT
Ravert
W B
WB
Mathews
Y
Y
Zhan
P A
PA
Finley
E D
ED
London
R F
RF
Dannals
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D002250:Carbon Radioisotopes; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002250:Carbon Radioisotopes; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C082748:epibatidine