New potent A₁ adenosine receptor radioligands for positron emission tomography

详细信息    查看全文

• 作者：Sabrina Kreft ; Dirk Bier ; ^{d.bier@fz-juelich.de} ; Marcus H. Holschbach ; Annette Schulze ; Heinz H. Coenen
• 关键词：CPFPX ; 8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ; PET ; positron-emission-tomography ; CBCPM ; 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine ; CPMMCB ; 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine ; GPCR ; G-protein-coupled receptors ; CNS ; central nervous system ; DPCPX ; 1 ; 3-dipropyl-8-cyclopentylxanthine ; NMR ; nuclear magnetic resonance ; TLC ; thin layer chromatography ; CHO ; Chinese hamster ovary ; POM ; pivaloyloxymethyl ; DMB ; 2 ; 4-dimethoxybenzyl ; HPLC ; high
• 刊名：Nuclear Medicine and Biology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：44
• 期：Complete
• 页码：69-77
• 全文大小：1602 K
• 卷排序：44

文摘

8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is meanwhile an accepted receptor ligand to examine the A1 adenosine receptor (A1AR) in humans by positron emission tomography (PET). A major drawback of this compound is its rather fast metabolic degradation in vivo.Therefore two new xanthine derivatives, namely 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (CBCPM; 5) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (CPMMCB; 6) were designed and synthesized as potential alternatives to CPFPX. In membrane binding studies both compounds showed nanomolar affinity for the A1AR. In vitro autoradiographic studies of [18F]5 and [18F]6, using rat brain slices, showed the expected accumulation in regions known to have a high adenosine A1 receptor expression while exhibiting the necessary low unspecific binding. However, in vitro metabolite studies using human liver microsomes revealed a comparable metabolic degradation rate for both new xanthine derivatives and CPFPX.