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

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 (Ki) estimated for FP-(+)-DTBZ (using [ 3 H](±)-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 [ 18 F]FP-(+)-DTBZ exhibited a ratio of striatum (ST, target) to cerebellum (CB, background) of 4.51 at 30 minutes postinjection, which is a higher value than previously obtained with the racemic ligand [ 18 F]FP-(±)-DTBZ (ST/CB = 2.95). Brain extraction at 30 minutes after the tracer injection in mice showed that >95% of the radioactivity corresponded to the parent, non-metabolized, compound remaining in the striatum, 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, substania nigra, dorsal raphe and locus coerules). We also tested the selective labeling of this tracer at the dopamine neurons in unilaterallesioned mice (treated with 6-hydroxydopamine). When [ 18 F]FP-(+)-DTBZ and [ 125 I]IPT ((N-(3'-iodopropen-2'-yl)-2-beta-carbomethoxy-3-beta-(4-chlorophenyl)tropane, a selective marker for dopamine transporters 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 [ 18 F]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.

Whole-Body Biodistribution and Radiation Dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): A Novel Vesicular Monoamine Transporter 2 Imaging Agent

“…The high liver uptake in humans is consistent with the reported high values of 3.53 %ID/g in rat (33) and 24.6 %ID/g in mouse (16) studies. However, the hepatic clearance of radioactivity is slow, and only a small amount reaches the gallbladder up to 3 h after intravenous injection of 18 F-AV-133 in humans.…”

“…Optically pure 18 F-AV-133 was synthesized at the cyclotron facility of Chang Gung Memorial Hospital following the method described previously, with some modification (16). The radiochemical purity of 18 F-AV-133 determined by analytic high-performance liquid chromatography was greater than 98%, and the specific activity was 60-200 TBq/mmol at the end of synthesis.…”

“…1; supplemental materials are available online only at http:// jnm.snmjournals.org) with a longer physical half-life (T 1/2 ) of 110 min (vs. 20 min for 11 C) has been recently developed (15). 18 F-AV-133 displayed an excellent binding affinity (K i 5 0.11 nM, rat striatal homogenates) for VMAT2 (15,16). Successful imaging studies in rodents and monkeys using 18 F-AV-133 have been reported (17).…”

Mapping the Target Localization and Biodistribution of Non-Radiolabeled VMAT2 Ligands in rat Brain

“…When employed, appropriatelabeled compounds with short-lived radionuclides such as 11 C, 15 O, 13 N, and 18 F, PET can quantitate physiological processes in a non-invas iv e manner ( 7 ). (8,9). Studies with [ 18 F]AV-133 may allow the presymptomatic identification of individuals with disorders characterized by the degeneration of dopaminergic nigrostriatal afferents.…”

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands

“…However, [ 11 C]DTBZ has high nonspecific binding to the exocrine pancreas, suggesting that it may not be suitable for imaging beta-cell mass (24,25). An 18 F-labeled analog of DTBZ ([ 18 F]DTBZ) has been previously synthesized (26), and the longer half-life of 18 F (110 min versus 20 min for 11 C) facilitates imaging at longer intervals after radiotracer administration, allowing more time for clearance of unbound radiotracer, thereby possibly exhibiting lower nonspecific pancreatic binding.…”