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

• Applicant: Dr. Rares-Petru Moldovan
• Subject Area: Pharmacy ; Nuclear Medicine, Radiotherapy, Radiobiology ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405969525

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.

• DFG Programme: Research Grants