In vitro and In vivo evaluation of Radioiodinated (-) -m-iodovesamicol : Potential radioligand for diagnosing Alzheimer's disease.

本研究的目的是开发一种新的突触前胆碱能神经元作图剂。我们合成了在4-苯基哌啶部分位放射碘化的左旋异构体(-)-m-碘维酰胺（(-)mIV），并评价了[I-125] (-) -mIV对大鼠脑内维酰胺受体的体外和体内结合亲和力和特异性，进一步评价了[I-125] (-) -mIV在阿尔茨海默病模型大鼠体内的特性。在体外和体内，[I-125] (-) - miv对维萨霉素受体（乙酰胆碱转运体）的结合亲和力非常高，与(-)-维萨霉素的结合亲和力相当；对多巴胺、血清素、去甲肾上腺素、乙酰胆碱和sigma受体的结合亲和力较低。这些相似的结果来源于饱和结合研究；[I-125] (-) - miv的Kd （18.2nM）和Bmax （660 fmol/mg蛋白）与(-)-vesamicol （Kd=20-30nM,Bmax=334-516fmol/mg蛋白）相当。此外，使用[I-125] (-) - miv和[Tc-99m] HMPAO在阿尔茨海默病模型大鼠脑中的双示踪自显影显示，在单侧胆碱能去神经控制模型中，基底前脑病变同侧投射皮质中[I-125] (-) - miv的积累显著减少11%，该模型被认为是阿尔茨海默病的实验模型。各区域[I-125] (-) - miv累积减少率为11%，[Tc-99m] HMPAO累积减少率为4%，差异有统计学意义（P<0.01）。这些结果表明，放射性碘化(-)- miv可能作为一种有用的放射配体，用于定位突触前胆碱能神经元。

The purpose of this investigation is to develop a new presynaptic cholinergic neuron mapping agent. We synthesized levorotatory isomer (-) -m-iodovesamicol ((-) mIV) radioiodinated at the meta position of the 4-phenylpiperidine moiety and evaluated the in vitro and in vivo binding affinity and specificity of [I-125] (-) -mIV for the vesamicol receptor in rat brain, furthermore, evaluated the in vivo characteristics of [I-125] (-) -mIV in the model rat of Alzheimer's disease. In vitro and In vivo binding affinity of [I-125] (-) -mIV for the vesamicol receptor (acetylcholine transporter) was very high and comparable to that of (-) -vesamicol ; the binding affinity for dopamine, serotonin, noradrenaline, acetylcholine and sigma receptors was low. These similar results were derived from saturation binding study ; Kd (18.2nM) and Bmax (660 fmol/mg of protein) of [I-125] (-) -mIV were comparable to those of (-) -vesamicol (Kd=20-30nM,Bmax=334-516fmol/mg of protein). Furthermore, double-tracer autoradiograms using [I-125] (-) -mIV and [Tc-99m] HMPAO in model rat brain of Alzheimer's disease showed a significant 11% decrease of the accumulation of [I-125] (-) -mIV in the projection cortices ipsilateral to the basalforebrain lesion in a unilateral cholinergic denervation model, which is regarded as an experimental model of Alzheimer's disease. The difference between the decrease of the accumulation of [I-125] (-) -mIV (11%) and that of [Tc-99m] HMPAO (4%) in the regions was statistically significant (P<0.01). These results suggest that radioiodinated (-) -mIV may serve as a useful radioligand for mapping presynaptic cholinergic neurons.