Development of novel imidazole and indane-indole based PET radioligands for imaging of cannabinoid CB2 receptors

开发用于大麻素 CB2 受体成像的新型咪唑和茚满吲哚 PET 放射性配体

• 批准号: 405969525
• 负责人: Dr. Rares-Petru Moldovan
• 金额: --
• 依托单位: Forschungsstelle Leipzig - Interdisziplinäre Isotopenforschung -
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405969525?language=en
• 关键词: Development; novel; imidazole; indane; indole

Cannabinoid receptor type 2 (CB2) represent a target with increasing importance for neuroimaging due to its upregulation in various pathological conditions. Despite the high importance of targeting the CB2 receptors and considerable efforts of various working-groups, no suitable radiotracer has been reported to date. The goal of the research project is the design of an 18F-labeled CB2 PET-tracer with sub-nanomolar affinity and high selectivity, mandatory features due to the low expression level of the CB2 receptors in the healthy brain. Recently, the applicant developed the sub-nanomolar affine and highly selective fluorinated derivative 14a (CB2Ki = 0.3 nM), suitable for the late stage incorporation of the 18F-label. Its radiofluorination and in vivo/vitro assessment is one of the first, main goals of this project. In parallel, aiming at a derivative with improved drug-like properties for targeting brain, the molecule will be further modified. By performing the thoroughly elaborated SAR study, a new fluorinated derivative with superior properties for the in-vivo targeting the CB2 receeptors in the brain will be died. Its suitability to image CB2 receptors in diseased brain will be finally investigated in a murine mouse model of neuroinflamation induced by LPS. A second part of the project will focus on the development of a CB2 radiotracer based on the structure of (R)-N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-fluoro-1H-indole-2-carboxamide ((R)-(–)-15). Compound (R)-(–)-15 was selected from the literature as potential lead molecule due to its high affinity towards the CB2 receptors. Preliminary results confirmed a low nanomolar CB2 affinity and good selectivity of the (–) enantiomer. It contains a fluorine at the indole 5-position which is inactivated for the nucleophilic SN2 introduction of the 18F-label. Efforts to introduce the 18F-label at this position will consider the newest methods reported in the literature, for example by using hypervalent iodonium illides as leaving group. Aiming at higher CB2 affinity as well as higher radiofluorination yields under mild reactions conditions, more activated positions for SN2 will be investigated for the last step introduction of fluorine-18. The best compounds developed during this research project will be radiofluorinated and biologically investigated. Target specificity and pharmacokinetics of the radiolabeled CB2 ligands will be assessed in vitro and in vivo in wildtype animals. The suitability of CB2 PET-imaging to visualize neuroinflammatory processes by dynamic PET studies of the most promising CB2 radioligand will be evaluated in a murine model of neuroinflammation.The strategy elaborated in this research proposal is promising the development of the first radiotracer suitable for the in vivo imaging of the CB2 receptors with PET.

大麻素受体2型（CB 2）代表了一个目标，由于其在各种病理条件下上调神经影像学的重要性日益增加。尽管靶向CB 2受体的高度重要性和各种工作组的相当大的努力，迄今为止还没有报道合适的放射性示踪剂。该研究项目的目标是设计一种18F标记的CB 2 PET示踪剂，其具有亚纳摩尔亲和力和高选择性，由于健康大脑中CB 2受体的低表达水平而具有强制性特征。最近，申请人开发了亚纳摩尔级的亲和和高选择性的氟化衍生物14 a（CB 2Ki = 0.3 nM），适用于18 F标记的后期掺入。其放射性和体内/体外评估是该项目的首要目标之一。与此同时，针对具有改进的用于靶向脑的药物样性质的衍生物，该分子将被进一步修饰。通过进行详细的SAR研究，将得到一种新的具有上级特性的氟化衍生物，用于体内靶向脑中的CB 2受体。最终将在LPS诱导的神经炎症小鼠模型中研究其对患病脑中CB 2受体成像的适用性。该项目的第二部分将侧重于开发基于（R）-N-（6-氰基-2，2-二甲基-2，3-二氢-1H-茚-1-基）-5-氟-1H-吲哚-2-甲酰胺（（R）-（-）-15）结构的CB 2放射性示踪剂。从文献中选择化合物（R）-（-）-15作为潜在的先导分子，因为其对CB 2受体具有高亲和力。初步结果证实了低纳摩尔CB 2亲和力和良好的选择性的（-）对映异构体。它在吲哚5-位含有氟，该氟因亲核SN 2引入18F-标记而失活。在该位置引入18F标记的努力将考虑文献中报道的最新方法，例如通过使用高价碘鎓作为离去基团。为了在温和的反应条件下获得更高的CB 2亲和力以及更高的放射性同位素产率，将研究SN 2的更多活化位置以用于最后一步引入氟-18。在该研究项目中开发的最佳化合物将进行放射性氟化和生物学研究。将在野生型动物体内和体外评估放射性标记的CB 2配体的靶特异性和药代动力学。CB 2 PET成像可视化神经炎症过程的最有前途的CB 2放射性配体的动态PET研究的适用性将在神经inflammation.The策略阐述在这个研究提案的小鼠模型进行评估是有希望的第一个放射性示踪剂适合在体内成像的CB 2受体与PET的发展。