Mulholland G K, Wieland D M, Kilbourn M R, Frey K A, Sherman P S, Carey J E, Kuhl D E
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0552, USA.
Synapse. 1998 Nov;30(3):263-74. doi: 10.1002/(SICI)1098-2396(199811)30:3<263::AID-SYN4>3.0.CO;2-9.
Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]fluoroethoxybenzovesamicol, (-)-[18F] FEOBV,(-)-(2R,3R)-trans-2-hydroxy-3-(4-phenylpiperidino)-5-(2-[18F ]fluoroethoxy)-1,2,3,4-tetralin, a high affinity positron emitting ligand for the vesicular acetylcholine transporter, as a potential in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blocking studies, in vivo rodent brain autoradiography and metabolites were examined. (-)-[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. Both the cholinergic localization and curare-like effects of FEOBV were associated with the "(-)"-enantiomer exclusively. (-)-[18F]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)-3-PPP, or E-2020, indicating FEOBV, unlike other vesamicol analogs, did not interact in vivo with dopamine or sigma receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (-)-[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. Metabolic defluorination in rodents was modest, and analysis of brain tissue following tracer administration found FEOBV as the only extractable radioactive species. (-)-[18F]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may provide a noninvasive means to safely and accurately gauge the functional integrity of cholinergic synapses in man using PET.
大脑皮质和海马中胆碱能传递的丧失是阿尔茨海默病的一个特征，利用正电子发射断层扫描（PET）对大脑中功能性胆碱能突触进行可视化，可能是研究活体人类这种退行性疾病的一种有用方法。我们研究了[18F]氟乙氧基苄基维司那明，(-)-[18F]FEOBV，(-)-(2R,3R)-反式-2-羟基-3-(4-苯基哌啶基)-5-(2-[18F]氟乙氧基)-1,2,3,4-四氢萘，一种对囊泡乙酰胆碱转运体具有高亲和力的正电子发射配体，作为一种潜在的体内胆碱能突触定位剂。研究了啮齿动物的生物分布、剂量学、生物学效应的立体特异性、药理阻断研究、体内啮齿动物脑放射自显影以及代谢产物。静脉注射后，(-)-[18F]FEOBV在脑中的摄取很强，在5分钟时小鼠脑中摄取量为2.65%剂量/脑，且在随后时间区域定位与已知的突触前胆碱能标记物分布相匹配。FEOBV的胆碱能定位和箭毒样效应均仅与“(-)”对映体相关。用氟哌啶醇、(+)-3-PPP或E-2020预处理后，(-)-[18F]FEOBV在啮齿动物脑中的区域分布变化不大，这表明与其他维司那明类似物不同，FEOBV在体内不与多巴胺或西格玛受体系统相互作用。静脉注射(-)-[18F]FEOBV 3小时后大鼠脑放射自显影显示，在富含突触前胆碱能元件的脑区有高度定位。啮齿动物中的代谢性脱氟作用较小，示踪剂给药后对脑组织的分析发现FEOBV是唯一可提取的放射性物质。根据大鼠数据计算的(-)-[18F]FEOBV剂量学估计，可给人类注射10 mCi剂量。这些研究表明，FEOBV在体内能以高特异性描绘胆碱能区域，并且可能提供一种非侵入性手段，利用PET安全准确地评估人类胆碱能突触的功能完整性。
