Pharmacokinetics of [18F]fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain

Kilbourn, Michael R.; Hockley, Brian; Lee, Lihsueh; Hou, Catherine; Goswami, Rajesh; Ponde, Datta E.; Kung, Mei-Ping; Kung, Hank F.

doi:10.1016/j.nucmedbio.2007.01.007

« Previous Next »Nuclear Medicine and Biology
Volume 34, Issue 3 , Pages 233-237, April 2007

Pharmacokinetics of [¹⁸F]fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain☆

Michael R. Kilbourn
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA
- Corresponding author. Cyclotron and Radiochemistry Facility, University of Michigan, Ann Arbor, MI 48109, USA. Tel.: +1 734 763 9246.
Brian Hockley
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA
Lihsueh Lee
- Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA
Catherine Hou
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
Rajesh Goswami
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
Datta E. Ponde
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
Mei-Ping Kung
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA
Hank F. Kung
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

Received 13 November 2006; received in revised form 18 January 2007; accepted 21 January 2007.

Abstract

The specific binding and regional brain pharmacokinetics of new fluorine-18 ([¹⁸F])-labeled radioligands for the vesicular monoamine transporter (VMAT2) were examined in the rat and primate brain. In the rat, 9-[¹⁸F]fluoropropyl-(±)-9-O-desmethyldihydrotetrabenazine ([¹⁸F]FP-(±)-DTBZ) showed better specific binding in the striatum than either (+)-[¹¹C]dihydrotetrabenazine ((+)-[¹¹C]DTBZ) or 9-[¹⁸F]fluoroethyl-(±)-9-O-desmethyldihydrotetrabenazine ([¹⁸F]FE-(±)-DTBZ). Using microPET, the regional brain pharmacokinetics of [¹⁸F]FE-(±)-DTBZ, [¹⁸F]FP-(±)-DTBZ and (+)-[¹¹C]DTBZ were examined in the same monkey brain. (+)-[¹¹C]DTBZ and [¹⁸F]FP-(±)-DTBZ showed similar brain uptakes and pharmacokinetics, with similar maximum striatum-to-cerebellum ratios (STR/CBL=5.24 and 5.15, respectively) that were significantly better than obtained for [¹⁸F]FE-(±)-DTBZ (STR/CBL=2.55). Striatal distribution volume ratios calculated using Logan plot analysis confirmed the better specific binding for the fluoropropyl compound [distribution volume ratio (DVR)=3.32] vs. the fluoroethyl compound (DVR=2.37). Using the resolved single active isomer of the fluoropropyl compound, [¹⁸F]FP-(+)-DTBZ, even better specific to nonspecific distribution was obtained, yielding the highest distribution volume ratio (DVR=6.2) yet obtained for a VMAT2 ligand in any species. The binding of [¹⁸F]FP-(+)-DTBZ to the VMAT2 was shown to be reversible by administration of a competing dose of unlabeled tetrabenazine. Metabolic defluorination was slow and minor for the [¹⁸F]fluoroalkyl-DTBZ ligands. The characteristics of high specific binding ratio, reversibility, metabolic stability and longer half-life of the radionuclide make [¹⁸F]FP-(+)-DTBZ a promising alternative VMAT2 radioligand suitable for widespread use in human positron emission tomography studies of monoaminergic innervation of the brain.