In vivo evaluation of [123I]-8-[4-[2-(5-Iodothienyl)]-4-oxobutyl]-3-methyl-1-phenyl-1, 3, 8-triazaspiro [4.5] decan-4-one as a potential dopamine D2 receptor radioligand … (original) (raw)
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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
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1991
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 ...
Synthesis and radioiodination of selective ligands for the dopamine D3 receptor subtype
Bioorganic & Medicinal Chemistry Letters, 2004
Starting from FAUC 365, a series of iodine substituted heteroaryl carboxamides has been synthesized revealing high affinity and selectivity for the dopamine D3 receptor. Binding data showed a 15-560-fold selectivity for the dopamine D3 over D2. A 2,3-dichloro substitution pattern on the phenylpiperazine moiety led to the highest subtype selectivity, whereas the 2-methoxy substituted compounds showed superior D3 affinity. Suitable precursors were radioiodinated with high radiochemical yields (53-85%) leading to potential imaging agents for the D3 receptor by SPET.
Nuclear Medicine and Biology, 1999
We have developed radiotracers based on agonists that may potentially allow the in vivo assessment of the high affinity (HA) state of the dopamine D-2 receptors. The population of HA state, which is likely the functional state of the receptor, may be altered in certain diseases. We carried out radiosyntheses and evaluated the binding affinities, lipophilicity, and in vitro autoradiographic binding characteristics of three dopamine D-2 receptor agonists: (؎)-2-(N,N-dipropyl)amino-5-hydroxytetralin (5-OH-DPAT), (؎)-2-(Nphenethyl-N-propyl)amino-5-hydroxytetralin (PPHT), and (؎)-2-(N-cyclohexylethyl-N-propyl)amino-5hydroxytetralin (ZYY-339). In 3 H-spiperone assays using rat striata, ZYY-339 exhibited subnanomolar affinity for D-2 receptor sites (IC 50 ؍ 0.010 nM), PPHT was somewhat weaker (IC 50 ؍ 0.65 nM), and 5-OH-DPAT exhibited the weakest affinity (IC 50 ؍ 2.5 nM) of the three compounds. Radiosynthesis of these derivatives, 2-(N-propyl-N-1-11 C-propyl)amino-5-hydroxytetralin ( 11 C-5-OH-DPAT), 2
Nuclear Medicine and Biology, 1995
CIA-69024, (+)-1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-["C]methyl-l,2,3,4-tetrahydroisoquinoline, is a specific and selective dopamine Dl radiotracer. The in viuo biodistribution of this novel radioligand in mice showed a high uptake in the striatum (6.7%ID/g) at 5 min, followed by clearance with a half-life of 16.1 min. As a measure of specificity, the striatal/cerebellar ratio reached a maximum of 7.4 at 30 min post-injection. Radioactivity in the striatum was reduced to the level of the cerebellum by pre-adminstration of the Dl antagonist SCH 23390 (1 mg/kg). Pretreatment of mice with spiperone (D2), 7-hydroxydipropylaminotetralin (7-OH-DPAT) (D3), clozapine (D4), ketanserin (5-HT2/5-HT2C), mazindol (monoamine reuptake), prazosin (x,), and haloperidol (D2/(r) had no inhibitory effect on ["CIA-69024 uptake in the striatum. The dextrorotatory enantiomer of the dopamine antagonist butaclamol inhibited striatal uptake, while the less active isomer ( -)-butaclamol did not. ["CIA-69024 binding was inhibited by unlabeled A-69024 in a dose dependent manner (ED,, = 0.3 mg/kg) in the striatum while no change occurred in the cerebellum. ["CIA-69024 warrants further investigation as a PET ligand for examination of central dopamine Dl receptors in humans.
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.