Sobrio Franck, Debruyne Danièle, Dhilly Martine, Chazalviel Laurent, Camsonne Rudolphe, Kakiuchi Takeharu, Tsukada Hideo, Barré Louisa
DRM-DSV-CEA - UMR CEA FRE CNRS 2698, Centre Cyceron, BP 5229, F-14074 Caen, France.
Neurochem Int. 2005 May;46(6):479-88. doi: 10.1016/j.neuint.2004.12.003.
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.
美加明是一种广为人知的烟碱型乙酰胆碱受体（nAChRs）非特异性拮抗剂，用于治疗和精神药理学研究。制备了[(11)C]-美加明并将其评估为用于正电子发射断层扫描研究烟碱型乙酰胆碱受体的假定放射性配体。放射性合成包括在40分钟内对去甲基前体进行[(11)C]-甲基化，放射性化学产率经衰变校正后为30 - 40%。大鼠体内生物分布研究表明，放射性配体穿过血脑屏障（30分钟时为0.39%注入剂量），45分钟时仅从未代谢的示踪剂中回收了大脑中的放射性配体。大鼠体内离体放射自显影研究未显示出优先摄取，用美加明或烟碱受体抑制剂氯异吲哚铵预处理也未显示出明显的特异性结合。为了研究可能的物种差异和麻醉效果，对麻醉的狒狒和清醒的猕猴进行了体内正电子发射断层扫描（PET）研究。两种灵长类动物大脑中[(11)C]-美加明的区域分布呈现出与大鼠相似的动力学，放射性示踪剂给药后约45 - 50分钟达到稳态。清醒猕猴大脑中的摄取值比麻醉狒狒高两倍（丘脑：清醒猕猴中为0.258%注入剂量/(千克·毫升)，狒狒中为0.129%注入剂量/(千克·毫升)）。PET图像显示放射性分布在整个大脑中相当均匀，但灰质中的摄取略高于白质。饱和或置换研究未改变大脑分布。体内未能建立特异性结合的可能解释是在示踪剂之前给予的未标记配体对离子通道进行了长期的结构修饰。总之，[(11)C]-美加明不满足作为烟碱型乙酰胆碱受体PET示踪剂的要求。
