Quantification of alpha4beta2* nicotinic receptors in the rat brain with microPET and 2-[18F]F-A-85380

The radioligand 2-[(18)F]F-A-85380 has been used for PET studies of the alpha4beta2* subtype of nicotinic acetylcholine receptors (nAChRs) in the living brain of humans and nonhuman primates. In order to extend the capacity of microPET to quantify neuroreceptors in rat brain, we carried out studies of 2-[(18)F]F-A-85380 to measure the apparent binding potential BP* in individual rats, which were studied repeatedly over several months. Using a bolus-plus-infusion paradigm, 2-[(18)F]F-A-85380 (specific activity 20-1300 GBq/micromol) was administered intravenously over 8 to 9 h with K(bol) values of 350 to 440 min and a mean infusion rate of 0.03+/-0.01 nmol/kg/h. Studies included a 2-h nicotine infusion initiated 2 h before the end of scanning to displace specifically bound radioactivity. Steady state binding in brain was obtained within 5 h as defined by the occurrence of constant radioactivity concentrations in brain regions and constant, free arterial plasma levels of nonmetabolized radioligand. BP* averages (+/-SEM) for thalamus, forebrain, and cerebellum were 5.9+/-0.7, 2.6+/-0.4, and 1.0+/-0.1, respectively, which are consistent with the alpha4beta2* nAChR distribution in rat brain measured in vitro. Studies of receptor occupancy determined the ED(50) to be 0.29 nmol/kg/h. The demonstration that alpha4beta2* nAChRs are quantifiable in the rat brain using PET measurements, coupled with the ability to conduct longitudinal studies over several months in the same rats, suggests potential applications to studies of chronic nicotine use, its treatment, and abnormal functioning of alpha4beta2* receptors in a rat model.