Synthesis and Preclinical Evaluation of 11 CGNE-0877 as a Potential PET Radioligand for Imaging Brain Leucine-Rich Repeat Kinase 2

Leucine-rich repeat kinase 2 (LRRK2) plays a central role in the pathogenesis of Parkinson’s disease (PD), with pathogenic mutations leading to increased kinase activity. Consequently, LRRK2 has become a key therapeutic target in PD research. Although several candidate PET radioligands have been investigated for imaging brain LRRK2, only a few have shown good brain permeability and even these have exhibited limited specific binding to the target. In our search for an improved radioligand candidate, we identified GNE-0877 (28) as a highly potent and selective inhibitor for LRRK2 (Ki = 0.7 nM) with physicochemical properties favorable for brain penetration. We, therefore, synthesized an N-Boc-protected precursor (22) for labeling 28 with carbon-11 (t1/2 = 20.4 min) at the N-methyl position, which yielded 11C28 in a two-step radiosynthesis with high isolated yields (∼12–15%), excellent radiochemical purity (≥97%), and high molar activity (260–330 GBq/μmol). We evaluated 11C28 as a potential PET radioligand for imaging brain LRRK2 in rodent and monkey. The radioligand showed excellent stability in vitro and desirably moderate lipophilicity (measured logD7.4, 2.92). Following intravenous administration in rodents or monkey, 11C28 entered the brain rapidly reaching high peak uptake (∼4.0 SUV). In monkey, however, 11C28 showed slightly higher brain uptake and higher total volume of distribution (VT) under preblocking of LRRK2 with 28 than at baseline, indicating an absence of measurable specific binding to LRRK2, possibly due to low LRRK2 density in vivo or to insufficient radioligand affinity.