Synthesis, Structure–Activity Relationships, Radiofluorination, and Biological Evaluation of [¹⁸F]RM365, a Novel Radioligand for Imaging the Human Cannabinoid Receptor Type 2 (CB2R) in the Brain with PET

Abstract

The development of cannabinoid receptor type 2 (CB2R) PET radioligands has been intensively explored due to the pronounced CB2R upregulation under various pathological conditions. Herein, we report on the synthesis of a series of CB2R affine fluorinated indole-2-carboxamide ligands. Compound RM365 was selected for PET radiotracer development due to its high CB2R affinity (K i = 2.1 nM) and selectivity over CB1R (factor > 300). Preliminary in vitro evaluation of [18F]­RM365 indicated species differences in the binding to CB2R (K D of 2.32 nM for the hCB2R vs K D > 10,000 nM for the rCB2R). Metabolism studies in mice revealed a high in vivo stability of [18F]­RM365. PET imaging in a rat model of local hCB2R­(D80N) overexpression in the brain demonstrates the ability of [18F]­RM365 to reach and selectively label the hCB2R­(D80N) with a high signal-to-background ratio. Thus, [18F]­RM365 is a very promising PET radioligand for the imaging of upregulated hCB2R expression under pathological conditions.

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…PET scans of a rat model with local hCB2R overexpression demonstrated that [ 18 F]5 was able to selectively and reversibly image cerebral CB2R. 6 Dominguez et al report [ 18 F]6 (Figure 1) targeting mutant Huntingtin (mHTT) aggregates in Huntington's disease. In vitro studies showed that 6 has higher mHTT specificity and human metabolic stability than the leading clinical ligand CHDI-180.…”

“…Moldovan et al report [ 18 F] 5 (Figure ) with high affinity toward human CB2R (hCB2R) and no or low affinity for rat CB2R. PET scans of a rat model with local hCB2R overexpression demonstrated that [ 18 F] 5 was able to selectively and reversibly image cerebral CB2R …”