Development of 18F/11C-Labeled Pyrrolo-Pyridine/Pyrimidine LRRK2 Selective PET Radioligands

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Background/Objectives: Leucine-rich repeat kinase 2 (LRRK2) is an enzyme implicated in Parkinson’s disease (PD) and a potential therapeutic target. LRRK2 PET radioligands could therefore function as imaging biomarkers for PD and as tools to measure enzyme occupancy of novel therapeutic candidates. This study aimed at developing novel radioligands for imaging using positron emission tomography (PET). Specific objectives were to synthesize fluorine-18-labeled pyrrolopyridine 1 ([18F]1), pyrrolo-pyrimidine 2 ([18F]2), as well as carbon-11-labeled pyrrolo-pyrimidine 3 ([11C]3), and examine their binding specificity, using in vitro autoradiography (ARG) and in vivo positron emission tomography (PET) imaging in non-human primates (NHPs). Methods: Radiolabeling was achieved either by classical one-step fluorine-18 nucleophilic substitution reaction or by methylation using carbon-11 methane. [18F]1 and [18F]2 were tested in NHP and human whole-hemisphere ARG experiments. PET imaging was performed in cynomolgus monkeys. Radiometabolites were measured in monkey plasma using gradient HPLC. Results: The results demonstrated successful radiolabeling of all three ligands. In ARG studies, both [18F]1 and [18F]2 displayed binding in brain slices from NHP and human samples. The binding of [18F]1 was blocked by cold Compound 1 and structurally distinct Compound 3, but not by the structurally distinct LRRK2 inhibitor PFE-360. On the other hand, the binding of [18F]2 was blocked by PFE-360 in certain regions of the brain, indicating some level of specific binding to LRRK2. All three ligands showed relevant brain uptake (>3%ID), with highest uptake being observed for [18F]1, particularly in the thalamus. In contrast, brain uptake of [18F]2 and [11C]3 was evenly distributed across all brain regions. No blocking effect of [18F]1 was observed after pretreatment with the structurally distinct LRRK2 inhibitors PFE-360 (0.5 mg/kg, iv) and GEN-7915 (40 mg/kg). Conclusions: PET imaging indicated a low in vivo specific binding of the radioligands in the cynomolgus monkey brain, suggesting that the radioligands are not suitable for LRRK2 imaging in vivo with PET. This study emphasizes the challenges in the development of PET radioligands for imaging LRRK2 and the need for additional work to achieve this goal.

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