~(18)F标记的白藜芦醇衍生物的合成及作为β-淀粉样斑块显像剂的初步评价

设计并合成四种白藜芦醇衍生物,以评价其用于Aβ-斑块PET显像的可能性。通过化学合成得到四种白藜芦醇衍生物的前体化合物和参比化合物;使用参比化合物测定其与Aβ1-42蛋白聚集体的体外结合性;经~(18)F]亲核取代反应对具有较高亲和力的化合物进行放化标记,并进行体外稳定性、脂水分配系数、生物分布等的测定。体外竞争结合实验显示化合物(E)-1-(3,5-二甲氧基苯乙烯基)-4-(2-(2-(2-氟乙氧基)乙氧基)乙氧基)苯(~(19)F]F-7)具有中度的结合性(Ki=43.76nmol/L);~(18)F]F-7的标记时间为32min,放化产率(未校正)为(23±2)%,经SEP PAK C18柱纯化后放化纯度大于95%,且在生理盐水中的稳定性大于3h,具有较好的脂溶性(lg P=3.08);生物分布实验显示化合物~(18)F]F-7具有较快的脑清除,注射后2min和60min的脑摄取分别为(0.55±0.05)%ID/g和(0.06±0.01)%ID/g,清除比达到9。化合物~(18)F]F-7是一种潜在的β-淀粉样斑块PET显像剂。

18F-Radiolabeled Resveratrol Derivatives: Synthesis,Radiolabeling, and Preliminary Evaluation as β-Amyloid Plaque PET Agents

In this study,four fluorine-substituted resveratrol derivatives were designed and synthesized as candidates for β-amyloid(Aβ) plaque imaging.The in vitro binding studies using Aβ1-42 peptide aggregates were carried out with the four resveratrol derivatives.The F-18 labeled derivatives with the highest binding affinities to Aβ1-42 aggregates were prepared using the appropriate mesylate precursors in DMSO,and the stability and partition coefficient were also evaluated.And the biodistribution studies were performed using the normal Kunming mice.Among all derivatives examined,(E)-1-(3,5-dimethoxystyryl)-4-(2-(2-(2-fluoroethoxy) ethoxy)ethoxy) benzene (Compound 7) shows highest binding affinity to Aβ1-42-peptide aggregates (Ki=43.76 nmol/L,with 125I]IMPY as radioligand).No-carrieradded 18F]F-7 was successfully prepared within 32 min (uncorrected yield (23±2)％) and purified using a Sep Pak C18 cartridge with a high radiochemical purity (＞95％).18F] F-7 shows a good stability in saline and an adequate lipophilicity (lg P=3.08).For biodistribution,18F]F-7 displays moderate initial brain uptake ((0.55 ± 0.05)％ID/g at 2 min) with rapid wash-out from brains ((0.06±0.01)％ID/g at 60 min);2-to-60 min uptake ratio is 9.Of these compounds,19 F] F-7 shows the highest binding affinity,and 18 F] F-7 exhibits suitable lipophilicity and reasonable initial brain uptake and fast washout.All these results indicate that 18F] F-7 is a suitable radioligand for Aβ plaque imaging.