Skaddan M B, Kilbourn M R, Snyder S E, Sherman P S, Desmond T J, Frey K A
Departments of Radiology and Neurology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0028, USA.
J Med Chem. 2000 Nov 16;43(23):4552-62. doi: 10.1021/jm000305o.
A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro K(i) values ranged from 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-piperidyl benzilate (3-FEPB, 22, K(i) = 12.1 nM) and N-(2-fluoroethyl)-4-piperidyl benzilate (4-FEPB, 8, K(i) = 1. 83 nM) were selected for radiolabeling with fluorine-18. Using alkylation with 2-[(18)F]fluoroethyl triflate, 3-[(18)F]FEPB (42) and 4-[(18)F]FEPB (43) were produced in 7-9% radiochemical yield and >97% radiochemical purity. For in vivo studies, retention was moderate in mouse brain for 42; however, blocking with scopolamine showed that uptake was not muscarinic cholinergic receptor-mediated. Conversely, 43 exhibited high, receptor-mediated retention in mouse brain, with significant clearance after 1 h. These results suggest that 43 could have applications as an in vivo probe for measuring endogenous acetylcholine levels.
以苯甲酰哌啶或苯甲酰吡咯烷支架为基础，由苯甲酰甲酯与4 - 哌啶醇、(R)-(+)-3 - 哌啶醇或(R)-(+)-3 - 吡咯烷醇制备了一系列31种化合物。胺取代基包括烷基和芳烷基。体外K(i)值范围为0.05 nM至>100 nM。选择(R)-N-(2 - 氟乙基)-3 - 哌啶基苯甲酸酯(3 - FEPB，22，K(i)=12.1 nM)和N-(2 - 氟乙基)-4 - 哌啶基苯甲酸酯(4 - FEPB，8，K(i)=1.83 nM)用氟 - 18进行放射性标记。通过用2 - [(18)F]氟乙基三氟甲磺酸酯进行烷基化反应，以7 - 9%的放射化学产率和>97%的放射化学纯度制备了3 - [(18)F]FEPB(42)和4 - [(18)F]FEPB(43)。对于体内研究，42在小鼠脑中的滞留适中；然而，用东莨菪碱阻断表明摄取不是由毒蕈碱胆碱能受体介导的。相反，43在小鼠脑中表现出高的、受体介导的滞留，1小时后有明显清除。这些结果表明43可作为测量内源性乙酰胆碱水平的体内探针。
