18F-desmethoxyfallypride: A fluorine-18 labeled radiotracer with properties similar to carbon-11 raclopride for pet imaging studies of dopamine D2 receptors

Abstract

We have developed (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-¹⁸F-fluoropropyl)-2-methoxybenzamide (¹⁸F-desmethoxyfallypride) as a fluorine-18 radiotracer with properties analogous to that of ¹¹C-raclopride. In vitro experiments in rat brain homogenates showed an association rate constant of 2.16 × 10⁸ M⁻¹min⁻¹ and a dissociation rate constant of 0.073 min⁻¹. High striatal uptake (up to 0.08% injected ,) of ¹⁸F-desmethoxyfallypride in rhesus monkeys was observed in PET experiments. The radiotracer cleared from the striata with a dissociation rate of 1.80 × 10⁻² min⁻¹. Striatum to cerebellum ratios peaked at 3.0 in 30 min after which they decreased steadily. Intravenously administered haloperidol displaced specifically bound ¹⁸F-desmethoxyfallypride with a k_off of 0.058 min⁻¹. Synaptic dopamine released by the treatment of the monkeys with d-amphetamine increased the dissociation rate of ¹⁸F-desmethoxyfallypride to 0.83 min⁻¹ thus reducing specifically bound ¹⁸F-desmethoxyfallypride by 56% over a period of 42 mins compared to a reduction of only 20% in controls during this time period. The sensitivity of ¹⁸F-desmethoxyfallypride towards competition with dopamine should make this radiotracer useful in PET studies to evaluate in vivo pharmacological effects of various agents that alter levels of endogenous dopamine.