In vivo [C-11]dihydrotetrabenazine binding in rat striatum: sensitivity to dopamine concentrations

Introduction: The sensitivity of the in vivo binding of [C-11]dihydrotetrabenazine ([C-11]DTBZ) and [C-11]methylphenidate ([C-11]MPH) to their respective targets - vesicular monoamine transporter type 2 (VMAT2) and neuronal membrane dopamine transporter after alterations in endogenous levels of dopamine was examined in the rat brain. Methods: In vivo binding of [C-11]DTBZ and [C-11]MPH was determined using a bolus+infusion protocol. The in vitro number of VMAT2 binding sites was determined by autoradiography. Results: Repeated dosing with alpha-methyl-p-tyrosine (AMPT) at doses that significantly (-75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [C-11]DTBZ binding to VMAT2 in the striatum. The increase in binding could be completely reversed via treatment with L-DOPA/benserazide to restore dopamine levels. There were no changes in the total number of VMAT2 binding sites, as measured using in vitro autoradiography. No changes were observed for in vivo [C-11]MPH binding to the dopamine transporter in the striatum following AMPT pretreatment. Conclusion: These results indicate that large reductions in dopamine concentrations in the rat brain can produce modest but significant changes in the binding of radioligands to VMAT2, which can be reversed by replenishment of dopamine using exogenous L-DOPA. (C) 2010 Elsevier Inc. All rights reserved.