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首页> 外文期刊>Life sciences >I-123-MSP and F[C-11]MSP: New selective 5-HT2A receptor radiopharmaceuticals for in vivo studies of neuronal 5-HT2 serotonin receptors. Synthesis, in vitro binding study with unlabelled analogues and preliminary in vivo evaluation in mice
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I-123-MSP and F[C-11]MSP: New selective 5-HT2A receptor radiopharmaceuticals for in vivo studies of neuronal 5-HT2 serotonin receptors. Synthesis, in vitro binding study with unlabelled analogues and preliminary in vivo evaluation in mice

机译：I-123-MSP和F [C-11] MSP：用于神经元5-HT2血清素受体体内研究的新型选择性5-HT2A受体放射性药物。合成，未标记类似物的体外结合研究和小鼠体内初步评估

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In vitro binding study on bovine brain membranes using [H-3]SCH23390, [H-3]spiperone, [H-3]prazosin and [H-3]RP62203 as radioligands (for D-1, D-2, alpha(1) and 5-HT2A receptors respectively) indicate that the new butyrophenones 8-[3-(4-fluorobenzoyl)propyl]-1-methyl- 1,3,8-triazaspiro[4,5]decan-4-one (FMSP) and 8-[3-(4-iodobenzoyl)propyl]- 1-methyl-1,3,8-triazaspiro[4,5]decan-4-one (IMSP) exhibit significantly higher selectivity for the 5-HT2A over D-1, D-2 and al receptors. Consequently, the radiolabelled analogues F[C-11]MSP and I-123-MSP were prepared in attempt to obtain potential radiopharmaceuticals for in vivo imaging of neuronal 5-HT2A receptors with positron emission tomography (PET) and single photon emission tomography (SPET). F[C-11]MSP was synthesized by reaction of [C-11]CH3I with 8-[3-(4-fluorobenzoyl)propyl]-1,3,8-triazaspiro[4,5]decan-4-one (DMSP) in 12 +/- 3 % radiochemical yield, whereas I-123-MSp was obtained in 82 +/- 8 % radiochemical yield by a no-carrier-added Cu(I)-assisted [I-123]iododebromination of 8-[3-(4-bromo-benzoyl)propyl]-1-methyl-1,3,8-triazaspiro[4,5]decan-4-one (BrMSP). In vivo pharmacokinetic and brain binding characterization of I-123-MSp assessed in mice following intravenous injection, showed a fast clearance of I-123-MSP from blood and relatively high initial uptakes in the liver, kidneys and in the lung. Significant uptake and long retention were observed in the brain (up to 1.64 % i.d., 60 min p.i.), with a regional accumulation of radioactivity consistent with the reported 5-HT2A receptors distribution in the brain. Frontal cortex to cerebellum ratio of 3.5 was calculated at 60 min p.i. Furthermore, the initial brain uptake was significantly reduced after pretreatment of the animals with ritanserin, a selective 5-HT2 antagonist, and by preinjection of the non-radiolabelled analog IMSP, thus indicating the specificity of the brain uptake. These data suggest that I-123-MSp may be a promising compound for studying the serotoninergic 5-HT2 receptors with SPET. Due to the low specific activity of F[C-11]MSP currently obtained by the [C-11]methylation reaction, systematic in vivo investigation of F[C-11]MSP are as yet not feasable. [References: 32]
机译：[H-3] SCH23390，[H-3] spiperone，[H-3] prazosin和[H-3] RP62203作为放射性配体对牛脑膜的体外结合研究（对于D-1，D-2，α（ 1）和5-HT2A受体）分别表明新的丁苯酮8- [3-（4-氟苯甲酰基）丙基] -1-甲基-1,3,8-三氮杂螺[4,5] decan-4-one（FMSP ）和8- [3-（4-碘苯甲酰基）丙基] -1-甲基-1,3,8-三氮杂螺[4,5] decan-4-one（IMSP）对D-HT2A的选择性比D高得多-1，D-2和Al受体。因此，制备了放射性标记的类似物F [C-11] MSP和I-123-MSP，试图获得潜在的放射性药物，以利用正电子发射断层扫描（PET）和单光子发射断层扫描（SPET）对神经元5-HT2A受体进行体内成像。 ）。 F [C-11] MSP是通过[C-11] CH3I与8- [3-（4-氟苯甲酰基）丙基] -1,3,8-三氮杂螺[4,5] decan-4-one（ DMSP）的放射化学产率为12 +/- 3％，而无载体的Cu（I）辅助[I-123]碘代溴化8可以得到I-123-MSp的放射化学产率为82 +/- 8％。 -[[3-（4-溴-苯甲酰基）丙基] -1-甲基-1,3,8-三氮杂螺[4,5]癸-4-酮（BrMSP）。静脉注射后在小鼠中评估的I-123-MSp的体内药代动力学和脑部结合特征表明，I-123-MSP可从血液中快速清除，并且在肝脏，肾脏和肺中的初始摄取相对较高。在大脑中观察到了显着的摄取和长时间滞留（最高每天内在60分钟内达到1.64％内在），放射性的区域累积与所报道的5-HT2A受体在脑内的分布相一致。在60分钟p.i时，额叶皮质与小脑的比例为3.5。此外，在用利坦色林（一种选择性的5-HT 2拮抗剂）对动物进行预处理以及通过预先注射非放射性标记的类似物IMSP后，最初的大脑摄取显着降低，从而表明了大脑摄取的特异性。这些数据表明，I-123-MSp可能是用于利用SPET研究5-羟色胺能5-HT2受体的有前途的化合物。由于目前通过[C-11]甲基化反应获得的F [C-11] MSP的比活性低，因此尚无法进行F [C-11] MSP的系统体内研究。 [参考：32]

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