Optimization of 11C-Donepezil radiosynthesis to study pharmacokinetics of reversible acetylcholine esterase inhibitor

Objectives Donepezil is an acethylcholine esterase inhibitor and one of the major therapeutic drugs for Alzheimer’s decease (AD). Although it is widely used in AD patients, the pharmacokinetics of Donepezil remains unproven in vivo. We aimed to optimize the radiosynthesis of 11C-Donepezil from 11C-CH3OTf , to reduce the amount of precursor for economic efficiency and high specific activity, and to provide it for pharmacokinetic study.

Methods We tested the form of precursor (hydrochloride salt or non hydrochloride salt), the concentration of precursor (0.25~1.0 mg/ml), the amount of precursor solution (0.2 ml or 1.0 ml), and the amount of sodium hydroxide (NaOH) as the base.

Results Radiochemical yield (RCY) was less than 5% for hydrochloride salt precursor and over 30% for non hydrochloride salt precursor. RCY was over 30 % for 0.5 mg/ml or more of precursor concentration, but was less than 5% with 0.25 mg/ml. Good RCY (35%) resulted from 0.2 ml and 1.0 ml of volume amount of precursor solution. RCY more than 35% needed 9 times higher content of NaOH than that of precursor. With 0.5 mg/ml in acetone and 5 μl of 1M NaOH, we obtained 600 MBq of 11C-Donepezil (specific activity was about 150 GBq/μmol) within 30 min (20 microA and 30 min irradiation). 11C-Donepezil produced was injected to rats. Planar positron imaging system (PPIS) showed a distribution similar to that reported previously in ex vivo 14C-Donepezil study.

Conclusions We optimized the radiosynthesis of 11C-Donepezil by employing easy and reliable methods and succeeded to analyze whole body pharmacokinetics of 11C-Denepezil in rats. Detailed pharmacokinetics of 11C-donepezil can be evaluated in rat with PPIS and potentially in humans with PET.

Research Support This work was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology (No. 19591416), Japan