High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides (original) (raw)
1991, Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. "Iodopride" (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, "iclopride" (KD 0.23 nM) and "itopride" (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, "epidepride" (KD 0.057 nM) and "ioxipride" (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios ...
Sign up for access to the world's latest research
checkGet notified about relevant papers
checkSave papers to use in your research
checkJoin the discussion with peers
checkTrack your impact
Sign up for access to the world's latest research
Related papers
Journal of Medicinal Chemistry, 1988
From salicyclic acid, the two enantiomers of N-[ (l-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14 % radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide125 and chloramine-T gave [1251](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of ['%I](S)-Gb and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenate5 using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD = 1.2 IN) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [1261](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1,60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 recepton indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography. amine D-2 r e~e p t o r ,~'~ the receptor having been implicated in t h e antipsychotic action of neuroleptic agents. 4-[1251]Iodospiperone (2c) in comparison with tritiated spiperone, however, was shown not t o be a useful ligand for
Proceedings of the National Academy of Sciences, 1985
Two substituted benzamides, FLB 524 and raclopride, were labeled with "1C and examined for their possible use as ligands for positron emission tomography (PET)scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. ["C]Raclopride showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of ["C]raclopride in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. This and previous in vitro data indicate that ["C]raclopride binds selectively to striatal D-2 dopamine receptors. In healthy human subjects, ["C]raclopride binding in the caudate nucleus/putamen was 4-to 5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, ["1C]raclopride appears to be advantageous with regard to (i) specificity of binding to D-2 receptors, (ii) the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and (id) rapid association and reversibility of specific binding. ["1C]Raclopride should be a valuable tool for characterizing D-2 receptors in the brains of patients with neuropsychiatric disorders.
Synapse, 2010
4-(Dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzamide (WC-10), a Nphenyl piperazine analog, displays high affinity and moderate selectivity for dopamine D 3 receptors versus dopamine D 2 receptors Bioorg. Med. Chem. 13;[77][78][79][80][81][82][83][84][85][86][87]. In this study, WC-10 was radiolabeled with tritium (specific activity = 80 Ci/mmol) and quantitative autoradiography studies were conducted using rhesus monkey and Sprague-Dawley rat brain sections. K d values for the binding of [ 3 H]WC-10 to D 3 receptors obtained from quantitative autoradiography with rhesus monkey and rat brain sections are in agreement with K d values obtained from cloned human and rat receptors ). The D 2 selective antagonist [ 3 H]raclopride binds with 11-fold higher affinity to human HEK D 2L (K d = 1.6 nM) than HEK D 3 (K d = 18 nM) receptors; and [ 3 H]raclopride binds to rat Sf9 rD 2L receptors with a K d of 6.79 nM, a value that is 4-fold lower than binding to human HEK D 2L receptors and 2.5-fold higher than binding to rat Sf9 rD 3 receptors. In vitro quantitative autoradiography studies with [ 3 H]WC-10 and [ 3 H]raclopride were conducted on adult rat and rhesus monkey brain sections. A mathematical model for calculating the absolute densities of dopamine D 2 and D 3 receptors based on the in vitro receptor binding data of [ 3 H]WC-10 and [ 3 H]raclopride was developed.
Loading Preview
Sorry, preview is currently unavailable. You can download the paper by clicking the button above.