Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography (original) (raw)
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PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride
Psychopharmacology, 1987
Tracer doses of HC-SCH 23390 and HC-raclopride, selective Dl-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with 11C-SCH 23390, but not ~ aC-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of 11C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or eis(Z)-flupentixol decanoate.
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.
Synapse, 1993
Bilateral decreases in striatal %-raclopride binding were observed in adult female baboons with high resolution PET following administration of drugs that act centrally on dopaminergic neurons. At baseline and following administration of d-amphetamine (a dopamine-releasing drug), GBR-12909 (a potent dopamine reuptake inhibitor), or tetrabenazine (a biogenic amine depleting drug) PET scans of %-raclopride binding were obtained in a CTI 931 positron tomograph. In all studies, the ratio of the distribution volumes for the striatum to the cerebellum for llC-raclopride binding decreased significantly by a n average of 16.2% for d-amphetamine, 22.1% for GBR-12909, and 28.3% for tetrabenazine while there were no significant changes observed in the cerebellum or in the rate of systemic metabolism of the radiotracer. These decreases exceed the testhetest variability of striatal 'lC-raclopride binding measured in the same animals under identical experimental conditions . Together these studies demonstrate that PET measurements of striatal llC-raclopride binding can be used to indirectly and non-invasively monitor changes in synaptic dopamine concentrations that result from a variety of neurophysiologic mechanisms. o 1993 Wiley-Liss, Inc ~~~
Quantification of D2Like Dopamine Receptors in the Human Brain with 18F-Desmethoxyfallypride
2000
Substituted benzamides such as 11 C-raclopride or 123 I-iodobenzamide are selective radiotracers for PET and SPECT imaging of D 2 -like dopamine (DA) receptors. 18 F-Desmethoxyfallypride ( 18 F-DMFP) is a benzamide tracer with the advantage of an 18 F label. We optimized the synthesis and evaluated 18 F-DMFP in PET studies on healthy human volunteers. Methods: The affinity of DMFP for D 2 -like DA receptors was characterized in vitro using membrane preparations from rat striatum and the DA receptor ligand 3 H-spiperone. PET studies on 10 healthy human volunteers were performed using a whole-body PET scanner after injection of 214 Ϯ 54 MBq (mean Ϯ SD) 18 F-DMFP. Brain images were acquired dynamically over 124 min, and metabolite-corrected plasma activity was used as the input function. Data analysis was performed using several different approaches (compartmental, graphical, equilibrium methods). Results: The mean inhibition constant (K i ) of DMFP was 15 Ϯ 9 nmol/L. In human brain, the striatum-to-cerebellum ratio reached a maximum of about 4 between 60 and 120 min. When specific binding in the striatum was expressed as the difference between binding in the striatum and the cerebellum, it reached a maximum at approximately 60 min after injection and remained almost constant until the end of data acquisition. The ratio of specific striatal to nonspecific cerebellar binding was about 3:1 at 120 min after injection. A small, but significant specific tracer binding could also be detected in the thalamus. Treatment of a schizophrenic patient with a high dose (1,000 mg/d) of another substituted benzamide, amisulpride, resulted in a reduction of specific tracer uptake of about 90% in striatal regions. With regard to measured distribution volumes and binding potentials, there was an excellent agreement between all applied analytic methods. Conclusion: Our study demonstrates that 18 F-DMFP is a highly reliable tracer for PET imaging of D 2 -like DA receptors. It offers the major advantage that it can be used independently of an on-site cyclotron within a PET satellite network. Noninvasive analytic methods without blood sampling provide valid measurements of receptor quantities in human striatum. Because of the 18 F label and the favorable imaging properties, 18 F-DMFP could become an efficient substitute for 11 C-raclopride in a clinical context.
Synapse, 2004
We have evaluated the in vitro autoradiographic binding characteristics and in vivo brain distribution of two high-affinity dopamine D2/D3 receptor agonists, (Ϯ)-2-(N-phenethyl-N-1Ј-11 C-propyl)amino-5-hydroxytetralin ( 11 C-PPHT) and (Ϯ)-2-(Ncyclohexylethyl-N-1Ј-11 C-propyl)amino-5-hydroxytetralin ( 11 C-ZYY-339) in rodents and in monkeys using positron emission tomography (PET). In vitro autoradiograms in rat brain slices with 11 C-PPHT and 11 C-ZYY-339 revealed binding to dopaminergic regions in the striata, which was substantially (Ͼ90%) displaced by 10 M sulpiride. Striatal binding was also removed in the presence of 5-guanylylimidophosphate (Gpp(NH)p), indicative of binding of these radiotracers to the high-affinity (HA) state. The results of in vivo studies in rats exhibited binding of the two radiotracers to the striata (striata/ cerebellum approached 2 in 30 min). The regional selectivity to the striata was reduced by preadministration of haloperidol. PET studies in male rhesus monkeys using an ECAT EXACT HRϩ scanner indicated localization of 11 C-PPHT and 11 C-ZYY-339 in the striata and thalamus. Striata to cerebellum and thalamus to cerebellum ratios were low (1.5 and 1.3, respectively, at 30 min postinjection) for both 11 C-PPHT and 11 C-ZYY-339, apparently due to the slower nonspecific clearance from cerebellum. These findings with 11 C-PPHT and 11 C-ZYY-339 indicate the possibility of in vivo imaging of high-affinity state of dopamine D2/D3 receptors in both the striata and the thalamus. Synapse 54: 83-91, 2004.
11C]Cyclopropyl-FLB 457: A PET radioligand for low densities of dopamine D 2 receptors
Bioorganic & Medicinal Chemistry, 2008
a b s t r a c t (S)-5-Bromo-N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide (4) has picomolar in vitro binding affinity to D 2 receptor (K i (D 2 ) = 0.003 nM) with lower affinity to D 3 receptor (K i (D 3 ) = 0.22 nM). In this study, we describe radiosynthesis of [ 11 C]4 and evaluation of its binding characteristics in post-mortem human brain autoradiography and with PET in cynomolgus monkeys. The 11 C labelled 4 was synthesized by using [ 11 C]methyltriflate in a methylation reaction with its phenolic precursor with good incorporation yield (64 ± 11%, DCY) and high specific radioactivity >370 GBq/lmol (>10 000 Ci/mmol). In post-mortem human brain autoradiography [ 11 C]4 exhibited high specific binding in brain regions enriched with dopamine D 2 /D 3 receptors and low level of non-specific binding. In cynomolgus monkeys [ 11 C]4 exhibited high brain uptake reaching 4.4% ID at 7.5 min. The binding in the extrastriatal low density D 2 -receptor regions; thalamus and frontal, parietal, temporal, and occipital cortex, was clearly visible. Pre-treatment with raclopride (1 mg/kg as tartrate) caused high reduction of binding in extrastriatal regions, including cerebellum. [ 11 C]4 is a promising radioligand for imaging D 2 receptors in low density regions in brain.