Validation of 4-[18F]-ADAM as a SERT imaging agent using micro-PET and autoradiography

Serotonin transporters (SERTs) have been implicated in various neuropsychiatric disorders. We aim to validate 4-[18F]-ADAM (N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine) as a SERT imaging agent in rats using micro-positron emission tomography (micro-PET) and autoradiography. Sixty to ninety min after injecting 4-[18F]-ADAM, specific uptake ratios (SURs) were determined by micro-PET measurements in various brain regions of normal control rats. For n = 3, the SUR in the midbrain was 4.94 ± 0.16, for the hypothalamus it was 4.39 ± 0.031 and for the caudate it was 4.18 ± 0.53. The retention of 4-[18F]-ADAM in the hypothalamus and midbrain regions increased rapidly between 5 to 10 min after injection and declined thereafter. The SURs determined by autoradiography were: 9.31 ± 1.41 for the midbrain, 7.15 ± 1.45 for the hypothalamus and 5.22 ± 1.14 for the caudate putamen. Both micro-PET and autoradiography studies revealed a dose-dependent progressive inhibition of radioligand uptake in the frontal cortex, caudate putamen and hypothalamus in rats treated with 0.01 to 0.25 mg/kg paroxetine. A decrease in 4-[18F]-ADAM uptake of approximately 84% was observed in the midbrain of rats pretreated with 0.25 mg/kg paroxetine as compared to controls (4.94 ± 0.16 versus 0.80 ± 0.17, n = 3). Both 5,7-dihydroxytryptamine and p-chloroamphetamine-treated rats showed pronounced reduction in 4-[18F]-ADAM binding when compared to normal controls. Rats pretreated with p-chloroamphetamine exhibited significant inhibition of 4-[18F]-ADAM uptake in brain regions rich in SERT over a period of four weeks. Thus, 4-[18F]-ADAM is a SERT-specific radioligand that may be useful for evaluating neuropsychiatric conditions involving serotonergic dysfunction.