99mTc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma-2 Receptor Ligands for Tumor Imaging

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• 作者：Dan Li ; Yuanyuan Chen ; Xia Wang ; Winnie Deuther-Conrad ; Xin Chen ; Bing Jia ; Chengyan Dong ; J?rg Steinbach ; Peter Brust ; Boli Liu ; Hongmei Jia
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：934-946
• 全文大小：667K
• ISSN：1520-4804

文摘

We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline pharmacophore as σ₂ receptor ligands. Rhenium compound 20a possessed low nanomolar σ₂ receptor affinity (K_i = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D_2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [^99mTc]20b showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to σ receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [^99mTc]20b in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection.