Synthesis, ex vivo evaluation, and radiolabeling of potent 1,5-diphenylpyrrolidin-2-one cannabinoid subtype-1 receptor ligands as candidates for in vivo imaging.
Synthesis, ex vivo evaluation, and radiolabeling of potent 1,5-diphenylpyrrolidin-2-one cannabinoid subtype-1 receptor ligands as candidates for in vivo imaging.
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DOI：
10.1021/jm800416m
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发表时间：
2008-09-25
影响因子：
7.3
通讯作者：
Schaus JM
中科院分区：
文献类型：
--
作者：
Donohue SR;Krushinski JH;Pike VW;Chernet E;Phebus L;Chesterfield AK;Felder CC;Halldin C;Schaus JM
我们报道了[甲基-11 C]（3R，5 R）-5-（3-甲氧基-苯基）-3-（（R）-1-苯基-乙氨基）-1-（4-三氟甲基-苯基）-吡咯烷-2-酮（[11 C]8，[11 C]MePPEP）在体内与猴脑中大麻素1型（CB 1）受体高选择性结合。我们现在描述8和四种类似物的合成，即4-氟-苯基（16，FMEPPEP）、3-氟甲氧基（20，FMPEP）、3-氟甲氧基-d2（21，FMEP-d2）和3-氟-乙氧基类似物（22，FEPEP），并报道它们在设计用于鉴定适合用作PET配体的化合物的离体模型中的活性。这些配体在体外对CB 1受体显示出高的选择性效力（Kb < 1 nM）。每种配体（30 μg/kg，i. v.）在基线和预处理条件下（3，利莫那班，10 mg/kg，i. v.）并在稍后的时间用LC-MS检测在离体额叶皮层中定量。最大配体摄取量较高（22.6-48.0 ng/g）。在预处理下，最大脑摄取量大大降低（6.5-17.3纳克/克）。由于每种配体容易进入大脑并以高选择性结合到CB 1受体，因此我们随后建立并在此描述了产生具有足够活性的[11 C]8、[11 C]16和[18 F]20-22的方法，以用于体内评价作为候选PET放射性配体。
We have reported that [methyl-11C](3R,5R)-5-(3-methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one ([11C]8, [11C]MePPEP) binds with high selectivity to cannabinoid type-1 (CB1) receptors in monkey brain in vivo. We now describe the synthesis of 8 and four analogs, namely the 4-fluoro-phenyl (16, FMePPEP), 3-fluoromethoxy (20, FMPEP), 3-fluoromethoxy-d2 (21, FMPEP-d2) and 3-fluoro-ethoxy analogs (22, FEPEP), and report their activity in an ex vivo model designed to identify compounds suitable for use as PET ligands. These ligands showed high, selective potency at CB1 receptors in vitro (Kb < 1 nM). Each ligand (30 μg/kg, i.v.) was injected into rats under baseline and pretreatment conditions (3, rimonabant, 10 mg/kg, i.v.), and quantified at later times in frontal cortex ex vivo with LC-MS detection. Maximal ligand uptakes were high (22.6-48.0 ng/g). Under pretreatment, maximal brain uptakes were greatly reduced (6.5-17.3 ng/g). Since each ligand readily entered brain and bound with high selectivity to CB1 receptors, we then established and here describe methods to produce [11C]8, [11C]16 and [18F]20-22 in adequate activities for evaluation as candidate PET radioligands in vivo.
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影响因子：
3.6
作者：
HAHN, RC;TOMPKINS, J
通讯作者：
TOMPKINS, J
影响因子：
1.8
作者：
Iwata, R;Furumoto, S;Ishiwata, K
通讯作者：
Ishiwata, K
影响因子：
64.8
作者：
MUNRO, S;THOMAS, KL;ABUSHAAR, M
通讯作者：
ABUSHAAR, M
影响因子：
3.1
作者：
Laruelle, Marc;Slifstein, Mark;Huang, Yiyun
通讯作者：
Huang, Yiyun
影响因子：
1.8
作者：
Donohue, Sean R.;Halldin, Christer;Pike, Victor W.
通讯作者：
Pike, Victor W.