A PET STUDY OF DOPAMINERGIC ACTIVITY WITH ARMODAFINIL

Harvard Medical School, Boston MA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. AIMS: The stimulant modafinil and its active isomer r-modafinil (armodafinil) are approved for the treatment of narcolepsy and undergoing assessment to treat other neuropsychiatric disorders. Armodafinil is more potent, has a longer duration of action, and contains no inactive components. Both were designated atypical because of their unknown mechanism of action. In a PET imaging study in nonhuman primates, we reported that clinically relevant doses of modafinil occupied the dopamine (DAT) and norepinephrine (NET) transporters in living brain, conceivably elevating extracellular catecholamine levels in brain and nullifying its "atypical" designation. We now report whether these findings in primates extend to human brain with armodafinil. METHODS: Twelve human subjects were enrolled. Plasma armodafinil levels were obtained and in vivo armodafinil occupancy of the DAT in striatum was detected by (11C)altropane. Changes in extracellular dopamine were detected by indirect displacement of the D2 dopamine receptor agonist (11C)raclopride in human subjects. RESULTS: Armodafinil occupied striatal DAT (100 mg PO: 34 percent-40 percent, 1- 2.5 hrs, n=6;250 mg: 60 percent-percent, 1-2.5 hrs;n=6). Armodafinil resulted in modest increases in extracellular dopamine levels, at both doses. CONCLUSIONS: Armodafinil cccupancy of the DAT and elevation of extracellular dopamine in vivo further implicate the DAT as a therapeutic site of action. These findings validate our previous discovery in nonhuman primates, support evaluation of armodafinil for dopamine-related disorders, e.g. attention deficit hyperactivity disorder, highlight the therapeutic potential of low affinity DAT inhibitors, and possibly the abuse liability of this previously designated class of "atypical" drugs.