@misc{oai:repo.qst.go.jp:00076445,
 author = {Mori, Wakana and Mori, Wakana},
 month = {Jun},
 note = {Objectives: Leucine-rich repeat kinase 2 (LRRK2) has recently indicated as an important drug target for Parkinson's disease (PD) due to an apparent increased activity caused by mutations associated with familial PD. In brain, LRRK2is abundant mainly in the cerebral cortex, striatum and cerebellum. To elucidate the functional role and pharmacological characterization of LRRK2 in vivo, several radiotracers for imaging LRRK2 have been synthesized. However, there was no clinically-used PET tracer available for human brain until now. In this study, we synthesized 4-(6-18F-fluoro-4-(5-isopropoxy-1H-indazol-3-yl)pyridin-2-yl)morpholine (18F-1) as a new radiotracer for LRRK2 and performed preliminary evaluation by investigating in vitro binding and in vivo potentials of 18F-1 in the rat brain.
Methods: The standard compound 1 and the bromo precursor 2 for labeling were synthesized by 7- and 5-step reactions starting from commercially-available chemicals, respectively. The radiosynthesis of 18F-1 was performed by heating a solution of 2, 18F-KF, and DABCO in DMSO at 150 °C for 20 min, followed by treatment with 2 mol/mL HCl at 110 °C for 20 min. Then, we conducted small-animal PET scans for rats to examine the in vivo brain regional distribution.
Results: The standard compound 1and the bromo precursor 2 were obtained in total yields of 10-20%, respectively. The desired radiotracer 18F-1 was achieved in around 16% isolated radiochemical yield (relative to 18F-, non-decay corrected). The radiochemical purity of this radiotracer was greater than 97%, and the molar activity was higher than 125 GBq/μmol at the end of synthesis. No radiolysis was observed for the 18F-1 solution up to 180 min after formulation with saline containing 0.8% ascorbic acid. The logD value of 18F-1 was determined to 3.7, which indicated a high possibility of brain penetration.PET imaging study showed that 18F-1 could pass through blood-brain-barrier and the initial uptake reached 1.5 SUV in the rat brain. However, no significant regional difference in uptake of radioactivity was observed throughout the rat brain. 
Conclusions: A novel PET tracer 18F-1 was synthesized and obtained with applicable radioactivity yield and enough quality for the animal studies. PET imaging studies showed a high brain uptake but a low in vivo specific binding in the normal brain. An animal model would be useful for evaluating the suitability of 18F-1 as a PET tracer for imaging LRRK2. This radiotracercould also become a useful lead compound for the development of new PET imaging agent with more in vivo specific bindings to LRRK2 in the living brain., SNMMI2019Annual Meeting},
 title = {Synthesis and preliminary evaluation of a new radiotracer for the PET imaging of leucine rich repeat kinase 2 in brain},
 year = {2019}
}