Development of [18F]-Labeled Pyrazolo[4,3-e]-1,2,4- triazolo[1,5-c]pyrimidine (SCH442416) Analogs for the Imaging of Cerebral Adenosine A2A Receptors with Positron

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• 作者：Shivashankar Khanapur ; Soumen Paul ; Anup Shah ; Suresh Vatakuti ; Michel J. B. Koole ; Rolf Zijlma ; Rudi A. J. O. Dierckx ; Gert Luurtsema ; Prabha Garg ; Aren van Waarde ; Philip H. Elsinga
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6765-6780
• 全文大小：763K
• ISSN：1520-4804

文摘

Cerebral adenosine A_2A receptors (A_2ARs) are attractive therapeutic targets for the treatment of neurodegenerative and psychiatric disorders. We developed high affinity and selective compound 8 (SCH442416) analogs as in vivo probes for A_2ARs using PET. We observed the A_2AR-mediated accumulation of [¹⁸F]fluoropropyl ([¹⁸F]-10b) and [¹⁸F]fluoroethyl ([¹⁸F]-10a) derivatives of 8 in the brain. The striatum was clearly visualized in PET and in vitro autoradiography images of control animals and was no longer visible after pretreatment with the A_2AR subtype-selective antagonist KW6002. In vitro and in vivo metabolite analyses indicated the presence of hydrophilic (radio)metabolite(s), which are not expected to cross the blood-brain-barrier. [¹⁸F]-10b and [¹⁸F]-10a showed comparable striatum-to- cerebellum ratios (4.6 at 25 and 37 min post injection, respectively) and reversible binding in rat brains. We concluded that these compounds performed equally well, but their kinetics were slightly different. These molecules are potential tools for mapping cerebral A_2ARs with PET.