Development of high-affinity fluorinated ligands for cannabinoid subtype 2 receptor, and in vitro evaluation of a radioactive tracer for imaging.

The development of neurodegenerative diseases is associated with cerebral inflammation, which activates resident immune cells of the central nervous system (CNS), namely microglial cells that show an up-regulation of the cannabinoid subtype 2 receptor (CB2R) expression. Therefore our work aimed to design and synthesize a radiotracer for the detection of CB2R expression by positron emission tomography (PET) allowing an early diagnosis of neurodegenerative diseases. For the development of such a PET tracer, N-alkyl-substituted indole-3-yl-tetramethylcyclopropylketones served as lead structures due to their high CB2R potency and selectivity, allowing radiolabeling on the N-alkyl chain. To this end, eight novel fluorinated N-alkyl-indole-3-yl-tetramethylcyclopropylketones were synthesized, investigated in radioligand binding studies, and structure-activity relationships were evaluated. The most promising candidate was (1-(4-fluoropropyl)-1H-indole-3-yl)(2,2,3,3-tetramethyl-cyclopropyl)methanone (Ki: 7.88 nM at the CB2R, 3430 nM at cannabinoid subtype 1 receptor (CB1R)). A precursor was synthesized, radiofluorinated with no-carrier-added [18F]F- by nucleophilic substitution of a tosyl group, and the resulting PET ligand was purified, all being performed on a fully automated synthesis module. The tracer was produced in 34 ± 6% radiochemical yield within 2 h and with molar activities of up to 1500 GBq/µmol. A first preclinical evaluation was carried out including determination of logP, metabolic stability by liver microsomes, and autoradiography. The novel PET tracer for imaging CB2R showed promising results warranting subsequent clinical evaluation.

Alcohol-Supported Cu-Mediated 18F-Fluorination of Iodonium Salts under "Minimalist" Conditions.

In the era of personalized precision medicine, positron emission tomography (PET) and related hybrid methods like PET/CT and PET/MRI gain recognition as indispensable tools of clinical diagnostics. A broader implementation of these imaging modalities in clinical routine is closely dependent on the increased availability of established and emerging PET-tracers, which in turn could be accessible by the development of simple, reliable, and efficient radiolabeling procedures. A further requirement is a cGMP production of imaging probes in automated synthesis modules. Herein, a novel protocol for the efficient preparation of 18F-labeled aromatics via Cu-mediated radiofluorination of (aryl)(mesityl)iodonium salts without the need of evaporation steps is described. Labeled aromatics were prepared in high radiochemical yields simply by heating of iodonium [18F]fluorides with the Cu-mediator in methanolic DMF. The iodonium [18F]fluorides were prepared by direct elution of 18F- from an anion exchange resin with solutions of the corresponding precursors in MeOH/DMF. The practicality of the novel method was confirmed by the racemization-free production of radiolabeled fluorophenylalanines, including hitherto unknown 3-[18F]FPhe, in 22-69% isolated radiochemical yields as well as its direct implementation into a remote-controlled synthesis unit.