D2 RECEPTORS IN SCHIZOPHRENIA: OPTIMIZED PET LIGANDS

脑内多巴胺D2受体阻滞剂与 已经证明了精神抑制剂的抗精神病作用。 部位 抗精神病药的作用，即大脑多巴胺能系统或 D2受体的亚群，以及 多巴胺能功能和精神分裂症的病理生理学不是 知道的 虽然尸检研究报告说， 人纹状体和中脑核，纹状体D2的体内研究 精神分裂症受试者的受体的研究结果相互矛盾。 的 目前用于D2受体PET研究的配体，即 螺哌隆或雷氯必利不适合用于边缘系统或皮质的研究， 受体。 雷氯必利可能不适合测量纹状体D2 受体数量，因为竞争性取代内源性 多巴胺 本课题组合成并研究了碘化苯甲酰胺， 相对低的亲脂性，非常高的亲和力（KD = 25皮摩尔），和 D2受体的选择性，可用于标记边缘皮层 和纹状体D2受体。 通过仔细分析 取代苯甲酰胺的构效关系， 我们在将受体亲和力和亲脂性与 在体内脑摄取中，我们提出了一系列氟化苯甲酰胺， 对D2受体也应该具有非常高的效力和选择性 作为体内研究的最佳亲脂性。 未标记的配体将是 通过测定IC50进行综合和初步评价 抑制[3H]螺哌隆和[125I]阿替普利与纹状体结合 膜和log KW pH 7.5配体具有高亲和力和最佳的 亲脂性将用18F放射性标记。 体外药理学 它们在纹状体、边缘区和皮质中结合的表征 以确定其对D2的效价和特异性 受体的 对大鼠和猴子脑生物分布的体内研究将 以检查它们作为体内研究配体的适用性 纹状体和纹状体外D2受体的表达，并验证 示踪剂动力学模型需要在体内测量受体功能。 的 这些配体的可用性，适当的示踪剂动力学模型， 分辨率PET扫描仪（FWHM < 3 mm）应允许研究边缘系统和 精神分裂症受试者的皮质和纹状体D2受体，和 多巴胺能相关疾病患者。

A relationship between dopamine D2 receptor blockade in the brain and the antipsychotic effects of neuroleptics has been demonstrated. The site of action of neuroleptics, i.e. which cerebral dopaminergic system(s) or subset of D2 receptors, and the relationship between changes in dopaminergic function and the pathophysiology of schizophrenia are not known. While autopsy studies have reported increased receptor numbers in the striatum and nucleus accumbens in man, in vivo studies of striatal D2 receptor in schizophrenic subjects have given conflicting results. The ligands which are presently used in PET studies of the D2 receptor, i.e. spiperone or raclopride,are unsuitable for studies of limbic or cortical receptors. Raclopride may not be suitable for measurement of striatal D2 receptor numbers because of competitive displacement by endogenous dopamine. Our group has synthesized and studied iodinated benzamides with relatively low lipophilicity, very high affinity (KD = 25 picomolar), and selectivity for the D2 receptor that can be used to label limbic cortical and striatal D2 receptors in vitro and in vivo. Using a careful analysis of structure-activity relationships for substituted benzamides and the knowledge we have gained in relating receptor affinity and lipophilicity to in vivo brain uptake, we propose a series of fluorinated benzamides which should have very high potency and selectivity for the D2 receptor as well as optimal lipophilicity for in vivo studies. Unlabelled ligands will be synthesized and preliminary evaluation performed by determination of IC50's for inhibition of [3H] spiperone and [125I] epidepride binding to striatal membranes and log KW pH 7.5 Ligands with high affinity and optimal lipophilicity will be radiolabelled with 18F. In vitro pharmacological characterization of their binding in striatum, limbic regions and cortex will be performed to establish their potency and specificity for the D2 receptor. In vivo studies of brain biodistribution rats and monkeys will be performed to examine their suitability as ligands for the in vivo study of striatal and extrastriatal D2 receptors in man and to validate the use of tracer kinetic models needed to measure receptor function in vivo. The availability of these ligands, proper tracer kinetic models, and very high resolution PET scanners (FWHM < 3 mm) should allow study of limbic and cortical as well as striatal D2 receptors in schizophrenic subjects, and patients with dopaminergic related disorders.