Characterization of optically resolved 9-fluoropropyl-dihydrotetrabenazine as a potential PET imaging agent targeting vesicular monoamine transporters

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

doi:10.1016/j.nucmedbio.2006.12.005

« Previous Next »Nuclear Medicine and Biology
Volume 34, Issue 3 , Pages 239-246, April 2007

Characterization of optically resolved 9-fluoropropyl-dihydrotetrabenazine as a potential PET imaging agent targeting vesicular monoamine transporters

Mei-Ping Kung
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
Catherine Hou
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
Rajesh Goswami
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
Datta E. Ponde
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
Michael R. Kilbourn
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA
Hank F. Kung
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Corresponding author. Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA. Tel.: +1 215 662 3096; fax: +1 215 349 5035.

Received 12 October 2006; received in revised form 13 December 2006; accepted 25 December 2006.

Abstract

Labeling derivatives of dihydrotetrabenazine (DTBZ) with F-18 (T_1/2=110 min) instead of C-11 (T_1/2=20 min) would improve their utility and availability for imaging vesicular monoamine transporters (VMAT2) in clinical settings. The successful synthesis, reported previously, of two novel 9-fluoroalkyl(±)-DTBZ ligands prompted us to study the optically resolved active ligand 9-fluoropropyl-(+)-DTBZ (FP-(+)-DTBZ), which may have more promising characteristics. The inhibition constant (K_i) estimated for FP-(+)-DTBZ (using [³H](±)-DTBZ as the labeled ligand in rat striatal homogenates) showed a lower value as compared to the racemic FP-(±)-DTBZ (0.10±0.01 vs 0.19±0.04 nM). The inactive isomer, FP-(-)-DTBZ, displayed a much lower binding affinity with a K_i value >3000 nM. Biodistribution studies in mice after an iv injection of [¹⁸F]FP-(+)-DTBZ exhibited a ratio of striatum (ST, target) to cerebellum (CB, background) of 4.51 at 30 min postinjection, which is a higher value than previously obtained with the racemic ligand [¹⁸F]FP-(±)-DTBZ (ST/CB=2.95). Brain extraction at 30 min after the tracer injection in mice showed that >95% of the radioactivity corresponded to the parent, nonmetabolized, compound remaining in the ST, suggesting that the tracer has an excellent in vivo stability. Furthermore, localization of the tracer in the brain examined with ex vivo autoradiography displayed a typical distribution pattern consistent with VMAT2 sites. The highest labeling was observed in monoaminergic neuron regions (caudate putamen, olfactory tubercle, nucleus accumbens, substantia nigra, dorsal raphe and locus coerules). We also tested the selective labeling of this tracer at the dopamine neurons in unilateral-lesioned mice (treated with 6-hydroxydopamine). When [¹⁸F]FP-(+)-DTBZ and [¹²⁵I]IPT ((N-(3′-iodopropen-2′-yl)-2-beta-carbomethoxy-3-beta-(4-chlorophenyl)tropane, a selective marker for dopamine transporters (DATs) in dopaminergic neurons) were simultaneously injected into lesioned mice, we observed an excellent correlation (r=0.95) for these tracers. From these findings, we conclude that [¹⁸F]FP-(+)-DTBZ is a sensitive and selective tracer for VMAT2 binding sites and it may be useful for in vivo evaluation of diseases relating to changes of monoamine neuronal integrity.