title: Evaluation in rats and primates of [11C]-mecamylamine, a potential nicotinic acetylcholine receptor radioligand for positron emission tomography.
abstract: Mecamylamine is a well-described non specific antagonist of nicotinic acetylcholine receptors (nAChRs), used in therapy and in psychopharmacological studies. [(11)C]-Mecamylamine was prepared and evaluated as a putative radioligand for positron emission tomography to study nicotinic acetylcholine receptors. The radiosynthesis consisted in the [(11)C]-methylation of the desmethyl precursor within 40 min with 30-40% radiochemical yield decay corrected. Biodistribution studies in rats showed that radioligand crossed the blood-brain barrier (0.39% ID at 30 min) and only unmetabolized tracer was recovered from brain at 45 min. Ex vivo autoradiography studies in rats did not indicate preferential uptake, and pre-treatment mecamylamine or with chlorisondamine, an nicotinic receptor inhibitor, did not demonstrate a significant specific binding. To investigate possible specie differences and effects of anesthesia, in vivo positron emission tomography (PET) studies were carried out on anaesthetized baboons and conscious macaques. The regional brain distribution of [(11)C]-mecamylamine in the two species of primates exhibited similar kinetics as did the rat with steady state reached about 45-50 min after radiotracer administration. Uptake values were two-fold higher in brain of conscious macaque than in anaesthetized baboon (thalamus: 0.258% ID/(kg mL) in conscious macaques and 0.129% ID/(kg mL) in baboons). PET images showed a radioactivity distribution which was quite homogeneous throughout the brain but with somewhat higher uptake in grey matter than in white. Brain distribution was unaltered by saturation or displacement studies. Possible explanation for the failure to establish specific binding in vivo could be long-lived structural modifications of the ionotropic channel by the unlabeled ligand administered before the tracer. In conclusion, [(11)C]-mecamylamine did not satisfy the requirements for a PET tracer of nicotinic acetylcholine receptors.
authors.affiliation: DRM-DSV-CEA - UMR CEA FRE CNRS 2698, Centre Cyceron, BP 5229, F-14074 Caen, France. sobrio@cyceron.fr
authors.forename: Franck
authors.initials: F
authors.lastname: Sobrio
authors.forename: Danièle
authors.initials: D
authors.lastname: Debruyne
authors.forename: Martine
authors.initials: M
authors.lastname: Dhilly
authors.forename: Laurent
authors.initials: L
authors.lastname: Chazalviel
authors.forename: Rudolphe
authors.initials: R
authors.lastname: Camsonne
authors.forename: Takeharu
authors.initials: T
authors.lastname: Kakiuchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.forename: Louisa
authors.initials: L
authors.lastname: Barré
mesh_terms: D000758:Anesthesia; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002714:Chlorisondamine / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D008464:Mecamylamine / Q000378:metabolism / Q000493:pharmacokinetics*; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000493:pharmacokinetics; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013045:Species Specificity; D014851:Wakefulness
chemical_list: D000777:Anesthetics; D002250:Carbon Radioisotopes; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D002714:Chlorisondamine