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首页> 外文期刊>Life sciences >123I-MSP and F(11C)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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123I-MSP and F(11C)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：123I-MSP和F（11C）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，与未标记类似物的体外结合研究以及在小鼠中的初步体内评估。

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摘要

In vitro binding study on bovine brain membranes using [3H]SCH23390, [3H]spiperone, [3H]prazosin and [3H]RP62203 as radioligands (for D1, D2, alpha1 and 5-HT2A receptors respectively) indicate that the new butyrophenones 8-[3-(4-fluorobenzoyl)propyl]-1-methyl-1,3,8-triazaspiro[4,5]de can-4-one (FMSP) and 8-[3-(4-iodobenzoyl)propyl]-1-methyl-1,3,8-triazaspiro[4,5]deca n-4-one (IMSP) exhibit a significantly higher selectivity for the 5-HT2A over D1, D2 and alpha1 receptors. Consequently, the radiolabelled analogues F[11C]MSP and 123I-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[11C]MSP was synthesized by reaction of [11C]CH3I with 8-[3-(4-fluorobenzoyl)propyl]-1,3,8-triazaspiro[4,5]decan-4- one (DMSP) in 12 +/- 3% radiochemical yield, whereas 123I-MSP was obtained in 82 +/- 8% radiochemical yield by a no-carrier-added Cu(I)-assisted [123I]iododebromination of 8-[3-(4-bromo-benzoyl)propyl]-1-methyl-1,3,8-triazaspiro[4,5]de can-4-ene (BrMSP). In vivo pharmacokinetic and brain binding characterization of 123I-MSP assessed in mice following intravenous injection, showed a fast clearance of 123I-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 123I-MSP may be a promising compound for studying the serotoninergic 5-HT2 receptors with SPET. Due to the low specific activity of F[11C]MSP currently obtained by the [11C]methylation reaction, systematic in vivo investigation of F[11C]MSP are as yet not feasable.
机译：[3H] SCH23390，[3H] spiperone，[3H] prazosin和[3H] RP62203作为放射性配体（分别针对D1，D2，alpha1和5-HT2A受体）对牛脑膜的体外结合研究表明，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] de can-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]十氢化-4-酮（IMSP）对5-HT2A的选择性比D1，D2和alpha1受体高得多。因此，制备了放射性标记的类似物F [11C] MSP和123I-MSP，以期尝试通过正电子发射断层扫描（PET）和单光子发射断层扫描（SPET）获得神经元5-HT2A受体体内成像的潜在放射性药物。 F [11C] MSP是通过[11C] 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）在12中的反应合成的+/- 3％的放射化学收率，而123I-MSP通过无载体添加的Cu（I）辅助的[123I]碘代溴化8- [3-（4-溴）来获得82 +/- 8％的放射化学收率-苯甲酰基）丙基] -1-甲基-1,3,8-三氮杂螺[4,5] de can-4-ene（BrMSP）。静脉注射后在小鼠中评估的123I-MSP的体内药代动力学和脑部结合特征表明，血液中123I-MSP的清除速度很快，并且肝脏，肾脏和肺部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（每天最多60分钟，即i.d.达1.64％），放射性的区域性积累与报道的脑内5-HT2A受体分布相一致。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，123I-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[11C]甲基化反应获得的F [11C] MSP的比活性低，因此尚无法进行F [11C] MSP的系统体内研究。

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