DOPAMINE TRANSPORTER IMAGING WITH FLUORINE-18 PET

正电子发射断层扫描(PET)是一种灵敏、特异的无创成像技术，可以提供体内神经递质系统的功能状态信息。最近的效果集中在基于PET的放射性示踪剂的开发上，用于研究多巴胺转运体(DAT)的丰度和药理学。DAT密度和功能的改变与神经退行性疾病和神经精神疾病有关，如帕金森氏病、抑郁症、亨廷顿舞蹈症、精神分裂症和注意缺陷多动障碍(ADHD)。以前的研究主要集中在氟-18标记的托烷衍生物，如FP-CIT，其中托烷的N-甲基被[18F]氟丙基取代。在第一阶段项目中，我们表征了一系列新型含氟烷基托烷衍生物的脑单胺转运体结合亲和力，这些衍生物表现出比FP-CIT更高的DAT亲和力和选择性。这些新的配体是开发18F标记的用于人脑DAT临床成像的PET放射性示踪剂的有吸引力的候选者。 我们在这个第二阶段项目的目标是进一步合成和药理学评价新的-或O-氟烷基托烷衍生物，以期一步简化18F-放射性标记。将对最有希望的化合物的物理化学性质(亲脂性)进行评估。对于最有前景的化合物(S)，将开发一种简便、快速地合成18F标记托烷衍生物的方法。本系列中的先导化合物(目前为BRL-308)将在非人类灵长类动物中通过PET成像和药代动力学进行评估。 拟议的商业应用：如果用放射性核素标记用于断层成像，β-CIT的氟丙基类似物将是一种有用的放射性药物。[123I]FP-CIT目前正在向核医学界销售。[18F]FP-CIT用于PET成像的需求主要用于研究界。提供一种易于生产[18F]FP-CIT的试剂盒或相关的改进配体将满足这一需求。

Positron emission tomography (PET) is sensitive and specific non-invasive imaging technology that can provide information about the functional status of neurotransmitter system in-vivo. Recent effects have focused on the development of PET-based radiotracers for use in studies of the dopamine transporter (DAT) abundance and pharmacology. Changes in the density and function of DAT have been implicated in neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, major depression, Huntington's chorea, schizophrenia, and attention deficit-hyperactivity disorders (ADHD). Out earlier studies have focused on fluorine-18 labeled tropane derivatives, such as FP-CIT, in which the N-methyl group of the tropane was replaced by a [18F] fluoropropyl group. During the Phase I project, we characterized the cerebral monoamine transporter binding affinity of a series of novel fluoralkyl-containing tropane derivatives which showed higher DAT affinity and selectivity than FP-CIT. These new ligands are attractive candidates for development of 18F-labeled PET radiotracers for clinical imaging DAT in human brain. Our objectives on this Phase II project are to further synthesize and pharmacologically evaluate novel- or O-fluoroalkyl tropane derivatives with a view toward one-step simplified 18F-radiolabeling. The most promising compounds' physiochemical properties (lipophilicity) will be evaluated. A facile and rapid method of synthesis of 18F labeled tropane derivatives will be developed for the most promising compound(s). The lead compound in this series (presently BRL-308) will be evaluated by PET imaging and pharmacokinetics, in non-human primates. PROPOSED COMMERCIAL APPLICATIONS: The fluoropropyl analogue of beta-CIT will be a useful radiopharmaceutical if labeled with radionuclides for tomographic imaging. [123I] FP-CIT is currently being marketed for sale to the Nuclear Medicine community. There is a need for [18F] FP-CIT for PET imaging primarily for the research community. The availability of a kit for easy production of [18F] FP-CIT or related improved ligands will meet this need.