18F-Labelled pyrrolopyrimidines reveal brain leucine-rich repeat kinase 2 expression implicated in Parkinson's disease.

18F-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 pyrrolopyrimidine derivative PF-06447475 as the lead compound, two in vivo -stable 18F-labelled pyrrolopyrimidines ([18F] 1 and [18F] 2) were synthesized automatically at radiochemical yields 8–10% (non-decay-corrected) with molar activities of 0.95 and 0.5 GBq/μmol, 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 [18F] 1 in the olfactory bulb, striatum, and hippocampus than WT mice during microPET/CT imaging, consistent with immunohistology results of LRRK2 distribution. [11C]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, 18F-labelled pyrrolopyrimidines can reflect real-time LRRK2 expression changes implicated in Parkinson's disease, which paves the way for LRRK2-related neurodegenerative precise therapy. Image 1 • 18F-labeled pyrrolopyrimidines were evaluate as a very first series of 18F-labeled small-molecule positron emission tomography probes to targeting leucine-rich repeat kinase 2 (LRRK2). • Impressive radiosynthesis, targeting efficiency, and in vivo stability to determine LRRK2 expression in the brain. • Detect LRRK2-mutation-triggered neurodegenerative disorders in vivo. [ABSTRACT FROM AUTHOR]