Hydrophilic 99mTc-EC and nonlipophilic 99mTc- MAMA′-BA complexes, owing to the existing of intact blood-brain barrier (BBB) in vivo, cannot cross from blood to brain. Previous studies showed that insulin is selectively transported by receptor-mediated transcytosis through the brain capillary endothelial wall that makes up the BBB. In this paper, based on the characteristic of the insulin receptor enriched in brain capillary, the complexes of hydrophilic 99mTc-EC and nonlipophilic 99mTc-MAMA′-BA are conju- gated to insulin respectively. After purification, the radio- chemical purity of 99mTc-EC-insulin and 99mTc-MAMA′- BA-insulin was > 90% and the stability in vitro was good. Expectation for the special formulation can be internalized and endocytosed into the capillary membrane by the vec- tor-mediated brain delivery system, and transported 99mTc-labeled conjugate through the BBB in vivo, thus en- hancing brain uptake in mice. The biodistribution results of 99mTc-EC-insulin and 99mTc-MAMA′-BA-insulin in mice in- dicated that the brain uptake was higher than 99mTc-EC and 99mTc-MAMA′-BA to some extent. The ratios of brain uptake of 99mTc-EC-insulin to 99mTc-EC, 99mTc-MAMA′-BA-insulin to 99mTc-MAMA′-BA were 4―6 at 2 and 3 h post-injection respectively. In conclusion, the given results have illustrated a new way of brain uptake enhancing for nonlipophilic like complexes that have BBB delivery problems. It has a poten- tial value for the ongoing development of 99mTc-labeled ra- diopharmaceuticals for CNS receptors imaging.
LIU Fei FAN Caiyun ZHANG Jinming WANG Wushang LIU Boli
目的合成新的^(11)C 标记小分子苯并呋喃衍生物并研究其生物学性质。方法合成前体5-溴2-(4-胺基苯)苯并呋喃,用改良的^(11)CH_3I 法标记,生成5-溴-2-(4-N-^(11)C-甲胺基苯)-苯并呋喃,以柱色层法测标记率。正常小鼠尾静脉注射5-溴-2-(4-N-^(11)C-甲胺基苯)-苯并呋喃后不同时间处死,测每克组织百分注射剂量率(%ID/g)。结果改良^(11)CH_3I 法标记率为45%,放化纯大于95%。小鼠尾静脉注射药物后,放射性主要分布于肝和肾内,药物能迅速被脑摄取,2 min 达到3.2%ID/g,正常脑对其清除快于对碘的取代物,2与30 min 放射性摄取比值为1.34。结论 ^(11)C 标记小分子溴取代苯并呋喃衍生物,可作为β-淀粉样蛋白(Aβ)显像剂,其生物学性质明显优于碘的取代物。
As amyloid β (Aβ) is at the centre of pathogenesis of Alzheimer's disease (AD), Aβ aggregate-specific probes for in vivo studies of Aβ are potentially important for the early diagnosis and the assessment of new treatment strategies in the AD brain by noninvasive imaging. Several series of compounds derived from Congo red (CR) and Thioflavin T (ThT) have been evaluated as potential probes for the Aβ imaging. They include a diversity of core structures contributing to their affinities to Aβ. Small-molecule inhibi- tors were known to inhibit the formation of Aβ oligomers and fibrils. This inhibition has to be performed in such a way that these inhibitors bind to Aβ in the binding channel where Aβ-binding probes should sit. Therefore, several of them were used as novel core structures to develop Aβ probes, with their de- rivatives exhibiting good Aβ affinities. This approach will facilitate the design of a variety of candidates for Aβ probe molecules and anti-aggregation-therapeutic drugs. Moreover, the finding of Aβ probes with diverse core structures recognized by binding sites on Aβs will likely provide a promising per- spective for the design of 99mTc-labeled probe-derived molecules.
For the development of new ligands as potential imaging agents for the serotonin transporter (SERT),a series of diphenyl ether derivatives have been synthesized,characterized,and evaluated for their in vitro binding affinities to the SERT. Among the above compounds,2-(2-((dimethylamino)methyl)-4-fluoro-phenoxy)-5-bromobenzenamine (15) and 2-(2-((dimethylamino)methyl)-4-fluorophenoxy)-5-iodobenzene amine (16) show high binding affinities for the SERT with Ki values of 0.28 and 0.20 nmol·L-1,respectively. They can be further labeled with carbon-11,fluorine-18,iodine-123 or bromine-76,and evaluated as useful imaging agents for the SERT. Moreover,the study of the structure-activity relationship (SAR) provides some useful information for the future design of new ligands.
DEUTHER-CONRAD WinnieBRUST PeterSTEINBACH JrgVERCOUILLIE Johnny
