Synthesis and in Vitro and in Vivo Evaluation of 18F-Labeled Positron Emission Tomography (PET) Ligands for Imaging the Vesicular Acetylcholine Transporter

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• 作者：Zhude Tu*^† ; ; Simon M. N. Efange^‡ ; ; Jinbin Xu^† ; ; Shihong Li^† ; ; Lynne A. Jones^† ; ; Stanley M. Parsons^§ ; ; Robe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：March 12, 2009
• 年：2009
• 卷：52
• 期：5
• 页码：1358-1369
• 全文大小：344K
• 年卷期：v.52,no.5(March 12, 2009)
• ISSN：1520-4804

文摘

A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (±)-trans-2-Hydroxy-3-(4-(4-[¹⁸F]fluorobenzoyl)piperidino)tetralin (9e) has K_i values of 2.70 nM for VAChT, 191 nM for σ₁, and 251 nM for σ₂. The racemic precursor (9d) was resolved via chiral HPLC, and (±)-[¹⁸F]9e, (−)-[¹⁸F]9e, and (+)-[¹⁸F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [¹⁸F]/F⁻ and Kryptofix/K₂CO₃ in DMSO with radiochemical yields of 50−60% and specific activities of >2000 mCi/μmol. (−)-[¹⁸F]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (−)-[¹⁸F]9e in putamen versus cerebellum at 2 h p.i. (−)-[¹⁸F]9e has potential to be a PET tracer for clinical imaging of the VAChT.