18F-Labelled Pyrrolopyrimidines Reveal Brain Leucine-Rich Repeat Kinase 2 Expression Implicated in Parkinson's Disease

F-18-Labelled pyrrolopyrimidines were synthesized and evaluated as positron emission tomography (PET) probes to determine leucine-rich repeat kinase 2 (LRRK2) expression in the brain. With pyrrolopyr-imidine derivative PF-06447475 as the lead compound, two in vivo-stable F-18-labelled pyrrolopyrimidines ([F-18]1 and [F-18]2) were synthesized automatically at radiochemical yields 8-10% (non-decay-corrected) with molar activities of 0.95 and 0.5 GBq/mmol, respectively. The measured K-d of 6.90 nM for 1 and 14.27 nM for 2 demonstrated high affinities for LRRK2. The LRRK2 G2019S mice had higher uptakes (P < 0.01) of [F-18]1 in the olfactory bulb, striatum, and hippocampus than WT mice during microPET/CT imaging, consistent with immunohistology results of LRRK2 distribution. [C-11]CFT microPET/CT imaging demonstrated a lower expression of dopamine transporter in LRRK2 G2019S mice. Parkinson's disease-like deficits in dopamine transporter synthesis and cognitive declines were noticed along with LRRK2 expression increase in the olfactory bulb, striatum, and hippocampus. Therefore, F-18-labelled pyrrolopyrimidines can reflect real-time LRRK2 expression changes implicated in Parkinson's disease, which paves the way for LRRK2-related neurodegenerative precise therapy. (C) 2021 Elsevier Masson SAS. All rights reserved.