Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation.
Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation.
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DOI：
10.1016/j.nucmedbio.2009.12.012
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发表时间：
2010-05
影响因子：
3.1
通讯作者：
Mach RH
中科院分区：
文献类型：
--
作者：
Tu Z;Xu J;Jones LA;Li S;Mach RH
罂粟碱，1-（3，4-二甲氧基苄基）-6，7-二甲氧基异喹啉，是磷酸二酯酶10A（PDE 10A）的特异性抑制剂，对PDE 10A、PDE 3A和PDE 4D的IC 50值分别为36 nM、1，300 nM和320 nM，已成为研究PDE 10A生理作用的有用药物工具。在这里，我们报告的放射合成[11 C]罂粟碱和[11 C]罂粟碱作为一个潜在的PET放射性示踪剂成像PDE 10A在中枢神经系统中的体外和体内评价。用[11 C]碘甲烷对罂粟碱的去甲基前体进行O-甲基化反应，得到了罂粟碱的放射合成。[11 C]罂粟碱的放射化学产率约为70%，比活度> 10 Ci/μmol（EOB）。大鼠和猴脑切片的体外放射自显影研究显示[11 C]罂粟碱选择性结合PDE 10A富集区域：大鼠脑纹状体和恒河猴脑尾状核和壳核。5 min时[11 C]罂粟碱在大鼠体内的生物分布表明，最初在纹状体中的蓄积高于其他脑区，但洗脱迅速。在恒河猴中的microPET成像研究类似地显示了纹状体中的初始特异性摄取，[11 C]罂粟碱从脑中非常快速地清除。我们的初步评估表明，尽管罂粟碱的效用，在体外研究和作为一种药物工具，[11 C]罂粟碱是不是一个理想的放射性配体的PDE 10A在中枢神经系统的临床成像。具有更高的抑制PDE 10A的效力和改善的药代动力学性质的罂粟碱类似物对于用PET成像这种酶是必要的。
Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase 10A (PDE10A) with IC50 values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiological role of PDE10A. Here, we report the radiosynthesis of [11C]papaverine and the in vitro and in vivo evaluation of [11C]papaverine as a potential PET radiotracer for imaging PDE10A in the CNS. The radiosynthesis of papaverine with 11C was achieved by O-methylation of the corresponding des-methyl precursor with [11C]methyl iodide. [11C]papaverine was obtained with ~70% radiochemical yield and a specific activity > 10 Ci/μmol (EOB). In vitro autoradiography studies of rat and monkey brain sections revealed selective binding of [11C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [11C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. microPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [11C]papaverine from brain. Our initial evaluation suggests that despites papaverine’s utility for in vitro studies and as a pharmaceutical tool, [11C]papaverine is not an ideal radioligand for clinical imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.
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影响因子：
3.8
作者：
BROCHMAN.E;HIRAI, K
通讯作者：
HIRAI, K
影响因子：
3.2
作者：
Coskran, Timothy M.;Morton, Daniel;Stephenson, Diane T.
通讯作者：
Stephenson, Diane T.
影响因子：
2.9
作者：
Seeger, TF;Bartlett, B;Menniti, FS
通讯作者：
Menniti, FS
DOI：
10.1002/jlcr.2590100302
发表时间：
1974-01-01
期刊：
JOURNAL OF LABELLED COMPOUNDS
影响因子：
--
作者：
ITHAKISSIOS, SD;TSATSAS, G;TSOLIS, A
通讯作者：
TSOLIS, A
影响因子：
1.1
作者：
RAE, ID;SIMMONDS, PM
通讯作者：
SIMMONDS, PM