Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.107 (DAT)
 1,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymoxamine, a prodrug, is rapidly deacetylated in the plasma to give two phase I metabolites, DMAT and DAT, which are further sulpho- and glucuro-conjugated and then excreted mainly in the urine. In a cross-over study, the dose-dependence of the metabolite ratio was evaluated in nine healthy volunteers after three doses (120, 240, 480 mg) of thymoxamine-HCl. Regardless of the dose, DMAT and its glucuronide were not detected, while the amount of DMAT-sulphate was found to be proportional to the dose administered. Plasma levels of DAT were measurable in only four of the nine subjects after the 480 mg dose and showed great intersubject variability. The pharmacokinetics of both DAT-sulphate and DAT-glucuronide were dose-dependent. As the dose increased, the proportion of DAT undergoing sulphatation decreased; this saturation was compensated by glucuronidation.
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PMID:Pharmacokinetics of a prodrug thymoxamine: dose-dependence of the metabolite ratio in healthy subjects. 183 81

The E isomer of (123)I-2beta-carbomethoxy-3beta-(4-fluorophenyl)-N-(1-iodoprop-1-en-3-yl)nortropane (Altropane(R)) shows high affinity (IC(50) = 6.62 +/- 0.78 nmol) and selectivity (DA/5-HT = 25) for DAT sites in the striatum. Recently, dynamic SPECT studies in healthy volunteers and patients with Parkinson disease demonstrated that the kinetics of striatal accumulation followed a pattern that is characteristic of a reversible tracer with maximal accumulation within 30 min after injection. These findings suggested that radiolabeling Altropane with [(11)C] might provide an equivalent and complementary tracer for PET studies. [(127)I] Altropane was treated with HCl to hydrolyze the methyl ester bond and yield a precursor for [(11)C] labeling. Introduction of an [(11)C] methyl ester group was achieved by treatment with [(11)C] CH(3)I followed by HPLC purification. Five healthy rhesus monkeys were injected with approximately 10 mCi of [(127)I,(11)C] Altropane and dynamic PET images were acquired over 90 min. Arterial blood samples were collected in parallel with imaging and metabolite analysis was performed by HPLC. The PET and metabolite corrected arterial blood data were to calculate k(3)/k(4) by two methods: 1) nonlinear least-squares fitting, and 2) a linear graphical method for reversible ligands. The synthetic procedure yielded high specific activity tracer, >1,000 mCi/micro mole, with radiochemical purity >95%. Synthesis time was approximately 30 min. The PET images revealed excellent striatal definition, with clear separation of caudate nucleus and putamen and minimal accumulation in brain regions with high 5HT transporter density. Metabolite analysis demonstrated that at 60 min after injection, approximately 80% of circulating tracer was intact [(127)I,(11)C] Altropane and the remainder was converted to polar metabolites. Values for k(3)/k(4) calculated by two analysis methods were remarkably similar: Method 1, 3.48 +/- 0.41; Method 2, 3.77 +/- 0.45 (mean +/- SEM, t = 2.31, df = 8, P = 0.64). These results establish that Altropane has the important characteristics of: 1) rapid and specific striatal binding; 2) high selectivity for DA vs. 5-HT transporter sites; 3) reversible binding kinetics; 4) potential for multiple injection studies; 5) high efficiency labeling with either [(11)C] or [(123)I]; 6) applicability for both PET and SPECT. These properties make Altropane an important DAT ligand for both research and clinical applications.
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PMID:[(11)C, (127)I] Altropane: a highly selective ligand for PET imaging of dopamine transporter sites. 1116 84

2beta-Carbomethoxy-3beta-[4'-((Z)-2-iodoethenyl)phenyl]tropane (ZIET) and 2beta-carbomethoxy-3beta-[4'-((Z)-2-bromoethenyl)phenyl]tropane (ZBrET) were synthesized as well as their nortropane congeners ZIENT and ZBrENT. Binding affinities of these compounds were determined in cells transfected to express human SERT, DAT, and NET using [3H]citalopram, [125I]RTI-55, and [3H]nisoxetine, respectively. Both ZIET and ZBrET displayed high affinity for the SERT (Ki = 0.11 and 0.08 nM, respectively). The affinities of ZIET and ZBrET for the DAT were 200 and 38-fold lower, respectively, than for the SERT. [11C]ZIET and [11C]ZBrET were prepared by alkylation of their corresponding nortropanes with [11C]methyl iodide in approximately 30% radiochemical yield (decay-corrected to end of bombardment, EOB). High specific activity [123I]ZIET was synthesized in 33% radiochemical yield (decay-corrected) by treating the 2beta-carbomethoxy-3beta-[4'-((Z)-2-trimethylstannylethenyl)phenyl]tropane (3) with no carrier-added sodium [123I]iodide and hydrogen peroxide in ethanolic HCl. Biodistribution studies in rats indicated that [123I]ZIET enters the brain readily and accumulates in SERT-rich regions. Blocking studies performed in rats demonstrated that [123I]ZIET was selective and specific for SERT-rich regions (e.g. thalamus, brainstem, and striatum). MicroPET brain imaging studies in monkeys demonstrated that [11C]ZIET and [11C]ZBrET uptakes were selectivity localized in the putamen, midbrain, caudate, thalamus, pons, and medulla. Radioactivity in the regions of high SERT density of monkey brain was displaceable with citalopram except in the putamen and caudate. Radioactivity uptake in these DAT-rich regions was significantly displaceable either by preadministration of citalopram followed by injection of RTI-113 (or vice-versa) or by administration of a mixture of DAT and SERT ligands. In conclusion, the high yield, high specific activity, one-step radiolabeling method, high selectivity and favorable kinetics, and the good results obtained with [123I]ZIET in rats support the candidacy of [11C]ZIET for in vivo visualization and quantification of brain SERT.
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PMID:Synthesis, radiosynthesis, and biological evaluation of carbon-11 and iodine-123 labeled 2beta-carbomethoxy-3beta-[4'-((Z)-2-haloethenyl)phenyl]tropanes: candidate radioligands for in vivo imaging of the serotonin transporter. 1497 92

To survive, animals must constantly update the internal value of stimuli they encounter; a process referred to as incentive learning. Although there have been many studies investigating whether dopamine is necessary for reward, or for the association between stimuli and actions with rewards, less is known about the role of dopamine in the updating of the internal value of stimuli per se. We used a single-bottle forced-choice task to investigate the role of dopamine in learning the value of tastants. We show that dopamine transporter knock-out mice (DAT-KO), which have constitutively elevated dopamine levels, develop a more positive bias towards a hedonically positive tastant (sucrose 400 mM) than their wild-type littermates. Furthermore, when compared to wild-type littermates, DAT-KO mice develop a less negative bias towards a hedonically negative tastant (quinine HCl 10 mM). Importantly, these effects develop with training, because at the onset of training DAT-KO and wild-type mice display similar biases towards sucrose and quinine. These data suggest that dopamine levels can modulate the updating of tastant values, a finding with implications for understanding sensory-specific motivation and reward seeking.
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PMID:Dopamine levels modulate the updating of tastant values. 1684 82