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

Kilbourn, Michael R.; Butch, Elizabeth R.; Desmond, Timothy; Sherman, Phillip; Harris, Paul E.; Frey, Kirk A.

doi:10.1016/j.nucmedbio.2009.08.013

« Previous Next »Nuclear Medicine and Biology
Volume 37, Issue 1 , Pages 3-8, January 2010

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

Michael R. Kilbourn
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Corresponding author. Cyclotron/Radiochemistry Facility, University of Michigan, Ann Arbor, MI 48109, USA. Tel.: +1 734 763 9246; fax: +1 734 615 2557.
Elizabeth R. Butch
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Timothy Desmond
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Phillip Sherman
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Paul E. Harris
- Department of Medicine, Columbia University Medical College, New York, NY 10032, USA
Kirk A. Frey
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

Received 23 July 2009; received in revised form 28 August 2009; accepted 31 August 2009. published online 05 October 2009.

Abstract

Introduction

The sensitivity of the in vivo binding of [¹¹C]dihydrotetrabenazine ([¹¹C]DTBZ) and [¹¹C]methylphenidate ([¹¹C]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 [¹¹C]DTBZ and [¹¹C]MPH was determined using a bolus+infusion protocol. The in vitro number of VMAT2 binding sites was determined by autoradiography.

Results

Repeated dosing with α-methyl-p-tyrosine (AMPT) at doses that significantly (−75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [¹¹C]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 [¹¹C]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.

Keywords: Tetrabenazine, Dopamine, Tomography, emission computed, Vesicular monoamine transporter, α-Methyl-p-tyrosine