Pet Imaging of Extrastriatial Dopamine Levels

描述(申请人提供)：大脑皮质、边缘区域和丘脑的多巴胺能神经传递被认为与精神分裂症、精神刺激性药物滥用和注意力缺陷障碍的病理生理学有关。虽然有PET和SPECT方法可以评估人的纹状体多巴胺(DA)释放和基线细胞外DA水平，但目前还没有有效的方法来研究MAN纹状体外区域的DA释放和基线细胞外DA水平。 [18F]FolyPride是一种非常有效和选择性的多巴胺D2放射性配基，即多巴胺D2受体的Kd值为31 pM，可用于描绘和定量人类纹状体、丘脑、边缘和皮质的多巴胺D2受体。对灵长类动物的研究表明，[18F]自豪感对纹状体和纹状体外区域释放的多巴胺水平很敏感。我们建议在12名正常受试者(年龄18-40岁，6岁，6岁)口服d-苯丙胺(0.43 mg/kg)之前和之后进行[18F]FolyPride PET研究，以研究d-苯丙胺诱导纹状体外区域多巴胺的释放。此剂量的真实d-苯丙胺可降低纹状体[11C]雷氯普利的结合电位，与静脉注射0.2-0.3 mg/kg剂量的d-苯丙胺相似，具有相似的变异性，但副作用较少且不严重。我们建议在12名正常受试者(年龄18-40岁，6岁，6岁)进行额外的[18F]FolyPride PET研究，在每24小时56.6 mg/kg的α-甲基副酪氨酸(70公斤受试者36小时内6克)疗程之前和之后进行，以估计纹状体外区域的基线细胞外多巴胺水平。估计纹状体外区域DA释放和基线细胞外DA水平的方法的发展将使一些精神和神经疾病的重要新研究成为可能，这可能使新的治疗干预措施的设计和评估成为可能。

DESCRIPTION (provided by applicant): Dopaminergic neurotransmission in cortex, limbic regions and thalamus is believed to be centrally involved in the pathophysiology of schizophrenia, psychostimulant drug abuse, and attention deficit disorder. While there are PET and SPECT methods for evaluating striatal dopamine (DA) release and baseline extracellular DA levels in man, at present there are no well validated methods for studying DA release and baseline extracellular DA levels in extrastriatal regions in man. [18F] fallypride is an extremely potent and selective dopamine D2 radioligand, i.e., a KD of 31 pM for the dopamine D2 receptor, which can be used do delineate and quantitate striatal, thalamic, limbic and cortical dopamine D2 receptors in man. Studies in primates demonstrate that [18F] fallypride is sensitive to levels of d-amphetamine released dopamine in both striatum and extrastriatal regions. We propose to perform [18F] fallypride PET studies in 12 normal subjects (ages 18-40, 6M, 6F) prior to and following d-amphetamine administration (0.43mg/kg orally) to study d-amphetamine induced dopamine release in extrastriatal regions. This dose of real d-amphetamine produces decrements in striatal [11C] raclopride binding potentials similar to those seen with a 0.2-0.3 mg/kg IV dose of d-amphetamine with similar variability, but with fewer and less severe side effects. We propose to perform additional [18F] fallypride PET studies in 12 normal subjects (ages 18-40, 6M, 6F) prior to and following a 36-hour course of 56.6 mg/kg alphamethylparatyrosine/24 hours (6 grams over 36 hours for a 70 kg subject) to estimate baseline extracellular dopamine levels in extrastriatal regions. The development of methods for estimating DA release and baseline extracellular DA levels in extrastriatal regions will allow important new research studies in a number of psychiatric and neurological disorders which may allow design and evaluation of new therapeutic interventions.