Potential of [¹⁸F]β‐CFT‐FE (2β‐carbomethoxy‐3β‐(4‐fluorophenyl)‐8‐(2‐[¹⁸F]fluoroethyl)nortropane) as a dopamine transporter ligand: A PET study in the conscious monkey brain

Abstract

A dopamine transporter (DAT) ligand 2beta-carbomethoxy-3beta-(4-fluoro-phenyl)-8-(2-[(18)F]fluoroethyl)nortropane ([(18)F]beta-CFT-FE) was synthesized and evaluated in comparison with [(11)C]beta-CFT in monkey brain using animal positron emission tomography (PET). [(18)F]beta-CFT-FE and [(11)C]beta-CFT were injected intravenously to conscious monkeys for a 91-min PET scan with arterial blood sampling for metabolite analysis. In the conscious state, [(18)F]beta-CFT-FE provided a peak about 20 min after the injection and declined thereafter in the striatum of monkey brain, while [(11)C]beta-CFT continuously increased with time up to 91 min after injection. Metabolite analysis revealed that [(18)F]beta-CFT-FE was more rapidly metabolized in plasma than [(11)C]beta-CFT. The striatal binding of both ligands was dose-dependently displaced by preadministration of a specific DAT inhibitor, GBR12909, at doses of 0.5 and 5 mg/kg; however, the displacement degree of [(11)C]beta-CFT-FE was higher than that of [(18)F]beta-CFT. The effects of the anesthetics, ketamine and isoflurane, on binding were more prominent in [(11)C]beta-CFT than [(18)F]beta-CFT-FE. Specificity and affinity of beta-CFT-FE to DAT were evaluated in an in vitro assay using cloned human DAT, serotonin transporter, and norepinephrine transporter in comparison with other conventional DAT ligands, showing that beta-CFT-FE had lower affinity and higher specificity to DAT than beta-CFT and beta-CIT. These results suggested that [(18)F]beta-CFT-FE could be a potential imaging agent for DAT, providing excellent selectivity and tracer kinetics for quantitative PET imaging.

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

“…The distribution pattern of [ 11 C]b-CFT was consistent with the previously reported DAT distribution determined in monkey brain with PET (Harada et al, 2004;Tsukada et al, 2001). There were no significant differences in the BP ND values of [ 11 C]b-CFT between baseline and ketamine administration in any brain regions ( Figure 2c).…”

“…In conscious monkeys and animal, PET anesthetic doses of ketamine significantly alter the synthesis rate of dopamine (Tsukada et al, 2000). Although dopamine D 2 receptor binding was decreased (Ohba et al, 2009;Onoe et al, 1994;Tsukada et al, 2000), dopamine transporter (DAT) availability is increased in living monkey brains (Harada et al, 2004;Tsukada et al, 2001). Although an inhibitory effect of ketamine on SERT was reported in vitro (Martin et al, 1990;Nishimura et al, 1998;Zhao and Sun, 2008), no one has evaluated the effects of subanesthetic doses of ketamine on SERT in vivo.…”

Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport

“…11 C]GR205171 studies, has been shown to moderately increase radioligand binding (Tsukada et al, 1999;Elfving et al, 2003;Harada et al, 2004). Both Hypnorm (VetaPharma Ltd.) and isoflurane anes- …”

Irreversible binding of a novel phenylisothiocyanate tropane analog to monoamine transporters in rat brain

“…Some of these have been evaluated preclinically and several are in clinical trials [12,13]. Radioligands synthesized from these compounds have been effective in vitro ligands for transporter binding [11,14,15] as well as PET ligands for in vivo imaging [16][17][18]. Furthermore, the structure-activity relationships of cocaine analogs have provided vital information to design specific molecular tools to characterize the structure and function of DAT, and to further explore its role in the pharmacology of cocaine.…”