Development of PET radioligands for cerebral cannabinoid receptor (CB1)

描述(申请人提供)：该提案的总体目标是开发一种用于人类受试者大脑大麻素受体(CB1)的正电子发射断层扫描(PET)定量成像的放射配基。迫切需要对CB1进行PET成像，以研究大麻系统在精神分裂症、抑郁症、肥胖症、药物依赖和许多其他疾病中的作用。目前，只有一种放射性配基可用于这一目的，并且其成像性能很差。R21：最近，我们团队开发了第一个具有合理性质的放射性配体[11C]JHU75528，用于动物CB1受体的定量PET成像。由于缺乏CB1受体的PET成像数据和很少的跨物种信息，尚不清楚[11C]JHU75528是否能令人满意地用于人类。在我们的初步研究过程中，我们合成了三个新的JHU75528类似物，它们的体外性能(结合亲和力和亲脂性)都优于JHU75528。在R21阶段，这些CB1配体将被用PET同位素进行放射性标记，并在狒狒身上测试它们的PET成像特性。将比较三种新型放射性配体和先前研究的[11C]JHU75528的狒狒PET成像性能。在此比较的基础上，R33期将选出两个脑摄取最好、结合电势值最大(BP&GT；1.3-1.5)、CB1受体密度高以及其他成像性能良好的放射性配基。R33：在该项目的R33阶段，将对两个候选放射性配基进行药代动力学、分布密度、结合潜力和CB1受体在狒狒脑中的占有率的量化。这两个候选放射性配体在啮齿动物中的辐射剂量测定和毒理学实验将与狒狒PET扫描同时进行，并将允许为这两个放射性配体提交医生赞助的探索性IND(EIND)。在FDA批准EIND后，将对两个放射性配基进行人体放射性示踪剂选择PET成像研究，以选择一个在人脑中具有最高结合潜力(BP&gt；1)和摄取的放射性配基。将获得最佳放射性配基的人体辐射剂量学。人体内的辐射剂量学数据将确保每个人体受试者进行两次或两次以上PET扫描时放射性配基的辐射安全性，并允许进行人体测试/重新测试PET扫描和Rimonabant的剂量依赖占用，Rimonabant是一种选择性的CB1拮抗剂，也是一种新兴的减肥药物。预计临床有效剂量的利莫那班将产生超过30%的入住率。这将证明这里开发的最好的放射性配体在人体内的饱和性，并说明它作为CB1的显像剂和未来治疗CB1药物开发的生物标记物的用途。开发用于大麻素1型受体(CB1)正电子发射断层扫描(PET)成像的放射性配体对于研究大麻素系统在神经精神障碍、肥胖、药物依赖和各种其他疾病中的作用以及开发治疗这些疾病的大麻能药物具有重要意义。

DESCRIPTION (provided by applicant): The overall objective of the proposal is to develop a radioligand for quantitative positron emission tomography (PET) imaging of the cerebral cannabinoid receptor (CB1) in human subjects. There is an urgent need for PET imaging of the CB1 to study the role of the cannabinoid system in schizophrenia, depression, obesity, drug dependence and many other disorders. Currently, only one radioligand is available for this purpose and its properties for imaging are poor. R21: Recently [11C]JHU75528, the first radioligand with reasonable properties for quantitative PET imaging of the CB1 receptor in animals, was developed by our group. Because of the lack of available data on PET imaging of the CB1 receptor and little cross-species information, it is not clear if [11C]JHU75528 will be satisfactory for use in humans. In the course of our Preliminary Studies, we synthesized three novel analogs of JHU75528 with in vitro properties (binding affinity and lipophilicity) superior to JHU75528. In the R21 phase these CB1 ligands will be radiolabeled with PET isotopes and tested for their PET imaging properties in baboon. The baboon PET imaging properties of three novel radioligands and the previously studied [11C]JHU75528 will be compared. Based on this comparison, the two radioligands with the best brain uptake, greatest values of binding potential (BP>1.3-1.5) in the baboon brain regions with high density of CB1 receptors and good other imaging properties will be selected for the R33 phase. R33: In the R33 phase of the project both candidate radioligands will be quantified for pharmacokinetics, distribution density, binding potential, and occupancy of the CB1 receptor in the baboon brain. Radiation dosimetry and toxicology experiments in rodents for both candidate radioligands will be conducted simultaneously with the baboon PET scans and will allow filing a physician-sponsored Exploratory IND (eIND) for these two radioligands. After the eIND approval by the FDA, the human radiotracer selection PET imaging studies with two radioligands will be performed to select the one radioligand with the highest binding potential (BP>1) and uptake in the human brain. Human radiation dosimetry will be obtained for the best radioligand. The radiation dosimetry data in humans will assure the radiation safety of the radioligand in two or more PET scans per human subject and allow carrying out human test/re-test PET scans and dose dependent occupancy of Rimonabant, a selective CB1 antagonist and an emerging anti-obesity drug. It is anticipated that clinically effective doses of Rimonabant will yield occupancy in excess of 30%. This will demonstrate in vivo saturability of the best developed here radioligand in humans and also illustrate its use as an imaging agent for the CB1 and as a biomarker in the future development of therapeutic CB1 drugs. Development of radioligands for positron emission tomography (PET) imaging of the cannabinoid receptors type 1 (CB1) is of great importance for studying the role of the cannabinoid system in neuropsychiatric disorders, obesity, drug dependence and a variety of other disorders as well as for developing cannabinergic medications to treat these conditions.