Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX):: A potent and selective A1-adenosine receptor antagonist for in vivo imaging
Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX):: A potent and selective A1-adenosine receptor antagonist for in vivo imaging
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DOI：
10.1021/jm020905i
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发表时间：
2002-11-07
影响因子：
7.3
通讯作者：
Coenen, HH
中科院分区：
文献类型：
--
作者：
Holschbach, MH;Olsson, RA;Coenen, HH
本文报道了含氟-18的新型腺苷受体(A(1)AR)拮抗剂[F-18]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine的前体合成和无载体加成(NCA)放射合成。前体对甲苯磺酸盐8-cyclopentyl-3-(3-tosyloxypropyl)-7-pivaloyloxymethyl-1-propylxanthine，2在氨基聚醚介导性条件下与NCA[F-18]KF进行亲核放射性氟化，然后去保护是简单的，并且在形成后，得到准备注射的放射性配体，放化产率为45+/-7%，放化纯度为98%，比放射性为>；270GBq/mumol(>；7.2Ci/mumol)。制备时间平均为55min。该合成方法对大批量生产具有较高的可靠性。常规生产(n=120次)的产量(类似于7.5GBq)。对放射性示踪剂进行了体内外药理评价，并对其在啮齿动物体内的药代动力学进行了详细的测定。静脉注射后，小鼠大脑的几个区域，包括丘脑、纹状体、皮质和小脑，出现了高水平的放射性蓄积。特异性A(1)AR拮抗剂8-环戊基-1，3-二丙基黄嘌呤(DPCPX)和N-6-环戊基-9-甲基腺嘌呤(N-0840)的拮抗作用，而与A(2)AR拮抗剂3，7-二甲基-1-丙基黄嘌呤(DMPX)的拮抗作用，表明放射性配基与A(1)AR在皮质和皮质下感兴趣区的特异性和可逆性结合。在小鼠血液中，至少有两种极性代谢物迅速形成(示踪剂应用后5分钟为50%)。然而，取60minpi的脑匀浆提取物的层析分析表明，98%的放射性是不变的放射性配基。对外周形成的放射性代谢物进行层析分离和重新注入，发现小鼠脑内没有放射性积累，这可能是由于代谢物的极性所致。这些初步结果表明，NCA[18F]CPFPX是一种有用的放射性配基，可用于脑A(1)AR的无创成像。
This report describes the precursor synthesis and the no-carrier-added (nca) radiosynthesis of the new A, adenosine receptor (A(1)AR) antagonist [F-18]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX), 3*, with fluorine-18 (half-life = 109.6 min). Nucleophilic radiofluorination of the precursor tosylate 8-cyclopentyl-3-(3-tosyloxypropyl)-7-pivaloyloxymethyl-1-propylxanthine, 2, with nca [F-18]KF under aminopolyether-mediated conditions (Kryptofix 2.2.2/K2CO3) followed by deprotection was straightforward and, after formulation, gave the radioligand ready for injection with a radiochemical yield of 45 +/- 7%, a radiochemical purity of >98% and a specific radioactivity of >270 GBq/mumol (>7.2 Ci/mumol). Preparation time averaged 55 min. The synthesis proved reliable for high batch. yields (similar to7.5 GBq) in routine production (n = 120 runs). The radiotracer was pharmacologically evaluated in vitro and in vivo and its pharmacokinetics in rodents determined in detail. After iv injection a high accumulation of radioactivity occurred in several regions of mouse brain including thalamus, striatum, cortex, and cerebellum. Antagonism by the specific A(1)AR antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and N-6-cyclopentyl-9-methyladenine (N-0840), but not with the A(2)AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), indicated specific and reversible binding of the radioligand to A(1)AR in cortical and subcortical regions of interest. In mouse blood at least two polar metabolites formed rapidly (50% at 5 min after tracer application). However, chromatographic analyses of brain homogenate extracts taken 60 min pi showed that >98% of radioactivity was unchanged radioligand. Chromatographic isolation and reinjection of peripherally formed radioactive metabolites revealed no accumulation of radioactivity in mouse brain, probably due to the polarity of the metabolites. These preliminary results suggest that nca [18F]CPFPX is a useful radioligand for the noninvasive imaging of the brain A(1)AR.