Synthesis and preclinical evaluation of [¹¹C]D617, a metabolite of (R)-[¹¹C]verapamil

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• 作者：Joost Verbeek^a ; ^{jverbeek@rnc.vu.nl} ; Stina Syvä ; nen^b ; Robert C. Schuit^a ; Jonas Eriksson^a ; Elizabeth C. de Lange^b ; Albert D. Windhorst^a ; Gert Luurtsema^a ; ¹ ; Adriaan A. Lammertsma^a
• 关键词：[11C]verapamil ; [11C]D617 ; P-glycoprotein ; PET ; Pgp ; Metabolite
• 刊名：Nuclear Medicine and Biology
• 出版年：2012
• 期刊代码：43_09698051
• 类别：ph
• 出版时间：May, 2012
• 卷：39
• 期：4
• 页码：530-539
• 文件大小：746 K

摘要

Objectives

(R)-[¹¹C]verapamil is widely used as a positron emission tomography (PET) tracer to evaluate P-glycoprotein (P-gp) functionality at the blood-brain barrier in man. A disadvantage of (R)-[¹¹C]verapamil is the fact that its main metabolite, [¹¹C]D617, also enters the brain. For quantitative analysis of (R)-[¹¹C]verapamil data, it has been assumed that the cerebral kinetics of (R)-[¹¹C]verapamil and [¹¹C]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[¹¹C]verapamil and [¹¹C]D617 are indeed similar and, if so, whether [¹¹C]D617 itself could serve as an alternative PET tracer for P-gp.

Methods

[¹¹C]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [¹¹C]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg路kg^鈭?, intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15聽mg路kg^鈭?, intravenously), as well as metabolite analysis (n=4).

Results

The precursor for the radiosynthesis of [¹¹C]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl-pentanitrile (desmethyl D617), was synthesized in 41%overall yield. [¹¹C]D617 was synthesized in 58%-77%decay-corrected yield with a radiochemical purity of 鈮?9%. The homogeneously distributed cerebral volume of distribution (V_T) of [¹¹C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment.

Conclusion

V_T of [¹¹C]D617 was comparable to that of (R)-[¹¹C]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[¹¹C]verapamil and [¹¹C]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar.