John C S, Gulden M E, Vilner B J, Bowen W D
Radiopharmaceutical Chemistry Section, George Washington University Medical Center, Washington, DC 20037, USA.
Nucl Med Biol. 1996 Aug;23(6):761-6. doi: 10.1016/0969-8051(96)00070-4.
N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-piperidinyl)ethylamine, IPEMP, and the corresponding bromo derivative, BrPEMP, have been synthesized and characterized. Both BrPEMP and IPEMP were evaluated for sigma-1 and sigma-2 subtype receptor affinities and found to possess very high affinities for both receptor subtypes. The precursor for radioiodination n-tributylstannylphenylethylpiperidinylethylamine was prepared from its bromo derivative by palladium-catalyzed stannylation reaction. Radioiodinated 4-[125I]PEMP was readily prepared in high yields and high specific activity by oxidative iododestannylation reaction using chloramine-T as oxidizing agent. Sites labeled by 4-[125I]PEMP in guinea pig brain membranes showed high affinity for BD1008, haloperidol, and (+)-pentazocine (Ki = 5.06 +/- 0.40, 32.6 +/- 2.75, and 48.1 +/- 8.60 nM, respectively), which is consistent with sigma receptor pharmacology. Competition binding studies of 4-[125I]PEMP in melanoma (A375) and MCF-7 breast cancer cells showed a high affinity, dose-dependent inhibition of binding with known sigma ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl) ethylamine, BD1008 (Ki = 5, 11 nM, respectively), supporting the labeling of sigma sites in these cells. Haloperidol, however showed a weaker (Ki = 100-200 nM) affinity for the sites labeled by 4-[125I]PEMP in these cells. Biodistribution studies of 4-[125I]PEMP in rats showed a fast clearance of this radiopharmaceutical from blood, liver, lung, and other organs. A co-injection of 4-IPEMP with 4-[125I]PEMP resulted in 37%, 69%, and 35% decrease in activity in liver, kidney, and brain (organs possessing sigma receptors), respectively at 1-h postinjection. These results suggest that 4-[125I]PEMP is a promising radiopharmaceutical for pursuing further studies in animal models with tumors.
已合成并表征了N-[2-(4-碘苯基)乙基]-N-甲基-2-(1-哌啶基)乙胺（IPEMP）及其相应的溴代衍生物（BrPEMP）。对BrPEMP和IPEMP进行了sigma-1和sigma-2亚型受体亲和力评估，发现它们对两种受体亚型均具有非常高的亲和力。放射性碘化的前体正三丁基锡苯基乙基哌啶基乙胺由其溴代衍生物通过钯催化的锡化反应制备。使用氯胺-T作为氧化剂，通过氧化碘去锡基反应，很容易以高收率和高比活度制备放射性碘化的4-[125I]PEMP。豚鼠脑膜中被4-[125I]PEMP标记的位点对BD1008、氟哌啶醇和(+)-喷他佐辛表现出高亲和力（Ki分别为5.06±0.40、32.6±2.75和48.1±8.60 nM），这与sigma受体药理学一致。4-[125I]PEMP在黑色素瘤（A375）和MCF-7乳腺癌细胞中的竞争结合研究表明，它与已知的sigma配体N-[2-(3,4-二氯苯基)乙基]-N-甲基-2-(1-吡咯烷基)乙胺（BD1008）具有高亲和力、剂量依赖性的结合抑制作用（Ki分别为5、11 nM），支持了这些细胞中sigma位点的标记。然而，氟哌啶醇对这些细胞中被4-[125I]PEMP标记的位点表现出较弱的亲和力（Ki = 100 - 200 nM）。4-[125I]PEMP在大鼠体内的生物分布研究表明，这种放射性药物能从血液、肝脏、肺和其他器官快速清除。在注射后1小时，将4-IPEMP与4-[125I]PEMP共同注射，导致肝脏、肾脏和大脑（具有sigma受体的器官）中的活性分别降低37%、69%和35%。这些结果表明，4-[125I]PEMP是一种有前景的放射性药物，可用于在肿瘤动物模型中进行进一步研究。
