The rate of dasotraline brain entry is slow following intravenous administration
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ORIGINAL INVESTIGATION
The rate of dasotraline brain entry is slow following intravenous administration Robert Lew 1 & Cristian C. Constantinescu 2 & Daniel Holden 3 & Richard E. Carson 3 & Vincent Carroll 2 & Gerald Galluppi 1 & Kenneth S. Koblan 1 & Seth C. Hopkins 1 Received: 13 February 2020 / Accepted: 27 July 2020 # The Author(s) 2020
Abstract Rationale Drugs that rapidly increase dopamine levels have an increased risk of abuse. Dasotraline (DAS) is a dopamine and norepinephrine reuptake inhibitor characterized by slow oral absorption with low potential for abuse. However, it remains unclear whether intravenous (i.v.) administration would facilitate the rapid elevation of dopamine levels associated with stimulant drugs. Objective To assess the kinetics of DAS across the blood-brain barrier and time to onset of dopamine transporters (DAT) inhibition. Methods We compared the onset of DAT occupancy and the associated elevation of synaptic dopamine levels in rhesus monkey following i.v. administration of DAS or methylphenidate (MPH) using positron emission tomography (PET). Brain entry times were estimated by reductions in [18F]-FE-PE2I binding to DAT in rhesus monkeys. Elevations of synaptic dopamine were estimated by reductions in [11C]-Raclopride binding to D2 receptors. Results Intravenous administration of DAS (0.1 and 0.2 mg/kg) resulted in striatal DAT occupancies of 54% and 68%, respectively; i.v. administered MPH (0.1 and 0.5 mg/kg) achieved occupancies of 69% and 88% respectively. Brain entry times of DAS (22 and 15 min, respectively) were longer than for MPH (3 and 2 min). Elevations in synaptic dopamine were similar for both DAS and MPH however the time for half-maximal displacement by MPH (t = 23 min) was 4-fold more rapid than for DAS (t = 88 min). Conclusions These results demonstrate that the pharmacodynamics effects of DAS on DAT occupancy and synaptic dopamine levels are more gradual in onset than those of MPH even with i.v. administration that is favored by recreational drug abusers. Keywords Dopamine transporter . Dopamine . Nonhuman primate . PET . [18F]-FE-PE2I . [11C]-Raclopride
Introduction The risk of recreational abuse of psychostimulant drugs is associated with drug administration that yields rapid and large increases in synaptic dopamine concentrations in key brain areas, particularly the ventral striatum. Recreational abusers may alter the route of self-administration to achieve more rapid
* Kenneth S. Koblan [email protected] 1
Sunovion Pharmaceuticals Inc., 84 Waterford Dr, Marlborough, MA 01752, USA
2
Invicro, 60 Temple St, Suite 8A, New Haven, CT 06510, USA
3
Department of Radiology and Biomedical Imaging, Yale University, P.O. Box 208048, New Haven, CT 06520, USA
delivery of drugs to the brain to induce multiple “highs.” Drug liking and abuse potential are higher when drugs such as cocaine or heroin are administered intravenously compared with other rapid modes of delivery such as insufflation (Resnick et al. 1977; Comer et al. 1999). Similarly, intravenous me
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