Poster Abstract #12: Brain and Plasma Pharmacokinetics of Three Dopamine Transporter (DAT)-Selective Blockers After Administration of a Range of Single Oral Doses in Conscious Mice

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Background and Objective Inhibition of dopamine reuptake via the dopamine transporter (DAT) present on CNS presynaptic dopaminergic neurons is a potential therapy for the treatment of Parkinson's disease (PD). DAT blockers have previously been shown to mitigate PD-like symptoms induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in nonhuman primates. This study evaluated brain penetration of three DAT-selective blockers, O-620 (difluoropine), O-1369, and O-2099, in mice after administration of single oral doses. Methods DAT blockers were administered in aqueous phosphate buffer (pH 3.0) by oral gavage at doses of 2, 5, 10, and 20 mg/kg to four groups of mice. Blood samples and whole brain specimens were taken at 0.5, 1, 2, 4, 6, 8, and 24 hours after the dose. Blood plasma and brain DAT blocker content used validated LC/MS/MS assay methodology. Pharmacokinetics analyses to determine elimination half-lives and area under the concentration vs. time (AUC) curves for plasma and brain were performed using WinNonlin software (Pharsight, Mountain View, CA). Results All three DAT blockers achieved rapid systemic and brain exposures ( C max and AUC) with maximal plasma and brain concentrations obtained within 0.5 hours. Half-lives ranged from 0.3 to 2.7 hours (plasma) and 0.3 to 3.3 hours (brain). Plasma mean C max values after doses of 2, 5, 10, and 20 mg/kg were 49.4, 128, 579, and 1338 ng/mL (O-620); 12, 19, 73, and 417 ng/mL (O-1369); and 172, 406, 759, and 1509 ng/mL (O-2099). Corresponding brain mean C max values were 377, 1547, 3348, and 9407 ng/g (O-620); 60, 131, 497, and 2584 ng/g (O-1369); and 447, 1049, 2594, and 6883 ng/g (O-2099). Mean brain-to-plasma concentration ratios and mean brain-to-plasma AUC ratios ranged from 2.2 to 17.6 and from 6.4 to 10.3, respectively, for O-620; from 5.3 to 8.3 and from 6.7 to 8.3, respectively, for O-1369; and from 2.2 to 17.7 and from 6.4 to 10.3, respectively, for O-2099. Conclusions DAT blockers have previously been shown to mitigate PD-like symptoms induced by MPTP in nonhuman primates. Here, we show that oral administration in mice of three DAT-selective blockers resulted in rapid absorption into the systemic circulation and the CNS. The CNS bioavailability and favorable brain-to-plasma ratios after oral dosing makes these DAT blockers attractive candidates for treatment of PD. The work described here was conducted by QPS, L.L.C., for Alseres Pharmaceuticals. The compounds tested were synthesized for Alseres Pharmaceuticals by Organix, Inc.