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PubMed1986

Synthesis of no-carrier-added N-([18F]fluoroalkyl)spiperone derivatives.

3-N-([18F]fluoroalkyl)spiperone derivatives (2,3) can be prepared by N-alkylation of spiperone (1) with fluoroalkyl halides. The fluoroalkylating species 2-[18F]fluoroethyl bromide (7), 3-[18F]fluoropropyl bromide (8) and 4-[18F]fluorobutyl bromide (9) were prepared by [18F]fluoride ion displacement of the corresponding trifluoromethanesulfonates (triflates 4,5,6). By this method, the 2-[18F]fluoroethyl-, 3-[18F]fluoropropyl-, and 4-[18F]fluorobutyl spiperone derivatives (2a-c) can be prepared and purified rapidly and conveniently, within 40 min, in yields of 30-40% (end of synthesis, EOS). An alternative approach, suitable for the preparation of 2-[18F]fluoroalkyl (ethyl, propyl, butyl, pentyl and hexyl) spiperone derivatives (3a-d), involves iodo[18F]fluorination of terminal olefins, followed by N-alkylation of spiperone. This sequence is less convenient and proceeds in lower overall yields (less than 5%).

Chromatography, High Pressure Liquid↗
PubMed1986

Syntheses and D2 receptor affinities of derivatives of spiperone containing aliphatic halogens.

The development of a high affinity dopamine receptor ligand labeled with the positron emitting radionuclide, 18F (t 1/2 = 110 min), is of considerable interest for imaging and quantification of dopamine receptors in vivo. Derivatives of spiperone, a dopamine antagonist, labeled with 18F have been prepared, but the syntheses either proceed with inefficient fluoride utilization or involve several synthetic steps subsequent to 18F incorporation. To date, only the short-lived radioisotope of carbon, 11C (t 1/2 = 20.4 min), has been efficiently incorporated in the final synthetic step of 3-N-[11C]methyl-spiperone. 3-N-Fluoroethyl, 3-N-chloroethyl, and 3-N-bromoethyl spiperone derivatives are prepared by alkylation of spiperone with the appropriate 2-tosyloxy ethyl halide. In addition, alpha-fluorospiperone, containing fluorine alpha to the butyrophenone carbonyl, has been prepared. The 3-N-haloethyl spiperones display high affinity for dopamine receptor in vitro. Incorporation of [18F]fluoride during the final synthetic step yields a high affinity, 18F-labeled dopamine receptor-binding ligand.

Animals↗
PubMed1991

Spiperone: a receptor ligand and/or a granular uptake tracer?

The accumulation of [3H]spiperone and [3H]dopamine was measured in striatum and pituitary gland slices of rat. Contrary to [3H]dopamine, [3H]spiperone storage was similar in striatum and pituitary gland. In addition, [3H]spiperone accumulation was not diminished by reserpine and tetrabenazine. These data show that spiperone is not subject to the granular uptake/storage mechanism and suggest that spiperone and its derivatives are specific ligands for dopamine receptors only.

Animals↗
PubMed1998

Characterization of [3H]5-hydroxytryptamine and [3H]spiperone binding sites in clathrin-coated vesicles from bovine brain.

Coated vesicles prepared from bovine brain cerebral cortex exhibited [3H]5-hydroxytryptamine (5-HT, serotonin) and [3H]spiperone binding activities. The binding activities were localized in the inner core vesicles. Binding reached an equilibrium level by 30-45 min at 30 degreesC, and was reversed by the addition of 100 microM 5-HT for [3H]5-HT binding or 10 microM ketanserin for [3H]spiperone binding. The saturation binding experiments indicated a single class of binding sites for [3H]5-HT and [3H]spiperone with apparent Kd values of 2.4 and 1.75 nM, respectively. The binding of [3H]5-HT was displaced by 5-HT and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), but not by ketanserin. The binding of [3H]spiperone was displaced by spiperone and ketanserin but not by 5-HT or 8-OH-DPAT even at 1 mM. The coated vesicles were shown by immunoblotting assay to contain alpha-subunits of GTP-binding proteins, Galphas, Galphai2, Galphai3, Galphao and Galphaq/11. Forskolin-stimulated adenylate cyclase activity in the coated vesicles was inhibited to 80% of the control level by 5-HT or 8-OH-DPAT. These results suggested that 5-HT1A and 5-HT2A receptors are present in bovine brain coated vesicles and that the 5-HT1A receptors are coupled to adenylate cyclase activity via GTP binding proteins.

Adenylyl Cyclases↗
PubMed1980

Biochemical properties of spiperone binding to rat brain membranes.

The biochemical properties of H-spiperone binding in vitro were studied systematically using a crude membrane homogenate of rat corpus striatum and separation by filtration. Scatchard analysis revealed a single high affinity site with a KD of 0.14 nM and Bmax of 26 fmol/mg of tissue. The dissociation constant obtained by measurements at equilibrium was similar to that obtained by measuring the rates of association and dissociation. The high affinity binding was stereospecific, thermolabile and highly pH dependent, being maximal from pH 7.6 to 7.8. Varying the concentration of Na+, Ca++, Mg++, Mn++, and Tris buffer had no significant effect on the amount of specific spiperone binding. Of the neurotransmitters, dopamine was the most potent inhibitor of specific spiperone binding, followed by serotonin, epinephrine, and norepinephrine. Apomorphine was more potent than dopamine, but less so than chlorpromazine and unlabelled spiperone. In eight regions of the rat brain, a direct correlation between the number of spiperone binding sites and the dopamine content of each region was demonstrated, while there were no major difference in KD values among these regions.

Animals↗
PubMed1985

Characterization of (3H)-spiperone binding to alpha 1-adrenergic receptors in a smooth muscle cell line.

Although (3H)-spiperone has been demonstrated to interact at both dopamine (D2) and serotonin (S2) receptors, it remains a popular choice for characterization of the D2-receptor using both in vitro and in vivo and in vivo assay techniques. Using a clonal smooth muscle cell culture line (DDT1 MF-2), which has previously viously been characterized as possessing alpha 1- and beta 2-adrenergic receptors, we have found that (3H)-spiperone also has a significant affinity for alpha 1-adrenergic receptors. Our results are consistent with other literature reports which have suggested that spiperone may interact at alpha 1-receptors and we have characterized this interaction. We have also found an additional, high affinity binding site for spiperone on these cells which may represent a D2 - receptor. Characterization of this high-affinity site has been difficult since it is present in very low density. We conclude that (3H)-spiperone binds with high affinity to at least three known neurotransmitter receptor sites: D2-dopamine, S2-serotoninn and alpha 1-adrenergic. The binding to the alpha 1-adrenergic receptor exhibits stereospecificity and a considerable degree of similarity in pharmacological profile to the D2-dopamine receptor.

Animals↗
PubMed1985

Synthesis of N-methyl and N-11C-methyl spiperone by phase transfer catalysis in anhydrous solvent.

Spiperone, a butyrophenone neuroleptic drug, has been used in binding studies of dopamine receptors. Långström et al. developed N-11C-methyl spiperone, and, in cooperate with Wagner et al., made it possible to visualize the distribution of dopamine receptors in the human brain in vivo. In this paper, we independently developed another synthetic method of N-11C-methyl spiperone using the phase transfer catalyst in an anhydrous solvent. Separation of the product is feasible only by passing the reactant solution through a Millipore filter and injecting it onto high pressure liquid chromatography (HPLC). The time required for the synthesis and purification of N-11C-methyl spiperone from 11C-methyl iodide and spiperone was 20 min. Radiochemical yield exceeded 35% against 11C-methyl iodide without correcting decay of the radioactivity.

Anhydrides↗
PubMed1988

Interaction of [3H]spiperone with rat striatal dopamine D-2 receptors: kinetic evidence for antagonist-induced formation of ternary complex.

The characteristics of [3H]spiperone interactions with rat striatal dopamine D-2 receptor were investigated. Although the association of [3H]spiperone occurred monoexponentially, the pseudo-first order rate constant of association showed a hyperbolic dependence on ligand concentration. The data were therefore analyzed with the assumption of a two-step binding reaction leading to ligand-induced receptor isomerization. For the first equilibrium, the dissociation constant (KD) was 1.2 nM, while for the second equilibrium, the association and the dissociation rate constants were 71.6 X 10(-3) sec-1 and 0.9 X 10(-3) sec-1, respectively. The dissociation rate constant of the overall binding reaction, as determined by inducing the dissociation of [3H]spiperone from its binding sites by 1 microM (+)-butaclamol, was 0.92 X 10(-3) sec-1. However, the kinetically derived KD (15 pM) of the binding reaction differed significantly from the KD (218 pM) obtained from equilibrium binding experiments. This inconsistency between the two KD values appeared to have arisen from using different receptor concentrations in deriving kinetic and equilibrium data. The KD of the equilibrium binding reaction indeed showed significant variation with the receptor concentrations in an inverse way, implicating the involvement of a third component in the two-step binding reaction to form a high affinity ternary complex rather than a simple ligand induced receptor isomerization. Pretreatment of the membrane with 0.1 mM guanosine 5'-imidodiphosphate [Gpp(NH)p] reduced the affinity of the equilibrium binding reaction to a value (KD = 1.2 nM) which corresponded to the kinetically derived KD of the first step of the binding reaction, indicating the involvement of a guanine nucleotide-binding protein or G protein in inducing the formation of the high affinity ternary complex. The affinity of the binding reaction in Gpp(NH)p-pretreated membranes, however, increased with the duration of incubation, indicating that the ligand receptor complex still can couple with the G protein even in the presence of Gpp(NH)p. Pretreatment of the membrane with pertussis toxin irreversibly decreased the affinity of the binding reaction without significantly affecting the total number of binding sites, implying the involvement of the Gi subclass of G protein in the interaction of [3H]spiperone with D-2 receptors. Inhibition of the [3H]spiperone binding by a dopamine receptor agonist, bromocriptine, also yielded a monophasic dose response curve both in the presence and in the absence of Gpp(NH)p.(ABSTRACT TRUNCATED AT 400 WORDS)

Algorithms↗
PubMed1985

[Binding of 3H-spiperone in the mouse brain after intraperitoneal injection].

In experiments on mice 3H-spiperone binding after intraperitoneal injection was studied. The binding of 3H-spiperone was saturable in the frontal cortex and subcortical structures, whereas in the cerebellum, the amount of radioactivity increased in a linear manner and was referred to as nonspecific binding. The neuroleptics haloperidol, chlorpromazine and sulpiride given 0.5 h before 3H-spiperone displaced 3H-spiperone in the subcortical structures in a dose-related manner. Although the level of the specific 3H-spiperone binding after intraperitoneal injection was lower than after intravenous injection, the intraperitoneal method is simpler, well reproduced and given results comparable with the intravenous method.

Animals↗
PubMed1989

Abnormal glucocorticoid dependent increase of spiperone binding sites on lymphocytes from schizophrenics in vitro.

The attempt was made to revise experimentally the concept of spiperone binding to human peripheral lymphocytes as a peripheral marker for schizophrenic disorder. Although it was not possible to detect differences in spiperone binding in freshly isolated lymphocytes from schizophrenics and controls, a significant increase in spiperone binding became apparent when the lymphocytes from patients were cultured in vitro in the presence of physiological concentrations of glucocorticoids. From our findings we have to assume that glucocorticoid-dependent regulation of the gene(s) containing the coding for spiperone binding sites could be functionally affected in distinct forms of schizophrenic psychosis. The glucocorticoid-induced increase of spiperone binding of human lymphocytes could represent a dynamic peripheral marker system. It further has to be investigated whether this concept of a regulatory dysfunction, as observed in lymphocytes from schizophrenic patients, can be applied to the CNS in general.

Adult↗
PubMed1998

Autoradiographic localisation of [3H]-SCH23390 and [3H]-spiperone binding sites in honey bee brain.

In the brain of the honey bee, dopamine receptors have been identified by using the vertebrate D1 dopamine antagonist [3H]-SCH23390 and the vertebrate D2 dopamine antagonist [3H]-spiperone. This study uses light microscope autoradiography to investigate the anatomical distributions of the binding sites labelled by [3H]-SCH23390 and [3H]-spiperone in tissue sections cut at three depths from the anterior surface of the brain. The binding of these radioligands differed significantly, in both density and distribution. Specific binding of [3H]-SCH23390, defined by using 5 x 10(-6) M cis-(Z)-flupentixol, was densest in regions of somata, such as the deutocerebral somatal rind, the somatal layer beneath the calyces of the mushroom bodies and the ventral protocerebral somatal group. High levels of [3H]-SCH23390 binding were also measured in the lateral protocerebrum. [3H]-Spiperone binding site density estimates were consistently lower than those of [3H]-SCH23390. Specific binding of [3H]-spiperone, determined by subtracting binding in the presence of 10(-4) M domperidone from the total binding, was highest in the alpha lobes, beta lobes, and calyces of the mushroom body neuropil. Relatively high binding was also measured in the central body and lateral protocerebral neuropil. These results suggest that the distribution of dopamine receptors in the brain of the bee is subtype specific, and they support the view that dopamine plays many roles in the insect central nervous system.

Animals↗
PubMed2005

Competitive MS binding assays for dopamine D2 receptors employing spiperone as a native marker.

A competitive MS binding assay employing spiperone as a native marker and a porcine striatal membrane fraction as a source for dopamine D2 receptors in a nonvolatile buffer has been established. Binding of the test compounds to the target was monitored by mass-spectrometric quantification of the nonbound marker, spiperone, in the supernatant of the binding samples obtained by centrifugation. A solid-phase extraction procedure was used for separating spiperone from ESI-MS-incompatible supernatant matrix components. Subsequently, the marker was reliably quantified by LC-ESI-MS-MS by using haloperidol as an internal standard. The affinities of the test compounds, the dopamine receptor antagonists (+)-butaclamol, chlorpromazine and (S)-sulpiride obtained from the competitive MS binding assay were verified by corresponding radioligand binding experiments with [3H]spiperone. The results of this study demonstrate that competitive MS binding assays represent a universally applicable alternative to conventional radioligand binding assays.

Animals↗
PubMed1983

[3H]spiperone binding sites in rat primary glial cultures, C6 glioma, and B104 neuroblastoma.

Binding sites for [3H]spiperone were detected on membranes from primary glial cultures from neonatal rat cortex and striatum and from the C6 glioma cells. [3H]Spiperone binding was displaceable by d-butaclamol. However, competition studies suggest that [3H]spiperone binding to primary glial cultures was mainly to serotonergic sites, and binding to the C6 glioma was alpha-adrenergic. No specific binding was detected to membranes from B104 neuroblastoma cells. Although [3H]spiperone binding to glial sites on whole striatum under generally used conditions is small (about 10%), the striatal glial hyperactivity that is often associated with neuronal degeneration could lead to an overestimation of presumed neuronal binding sites for dopaminergic ligands.

Animals↗
PubMed1979

Effects of spiperone on feeding performance in a food preference test.

Spiperone reduced latency to feed and prolonged the total duration of feeding in a food-preference test in which novel and familiar foods were presented simultaneously to food-deprived rats. The increase in feeding duration could be accounted for in terms of an increase in time devoted to eating the novel foods, leaving the time devoted to eating the familiar food relatively unaltered. However, closer analysis of the data revealed that, at the level of mean duration of individual eating episodes, spiperone prolonged the eating-episode duration equally for both novel and familiar foods. This apparent paradox was resolved by noting that whilst spiperone did not alter the number of eating episodes in the test, it did alter the ratio of eating episodes in favour of novel foods. The data was incorporated into a control system model which depicts actions of spiperone in the food-preference situation with total eating duration as the final behavioural output.

Animals↗
PubMed1989

Influence of the D-2 dopamine receptor agonist quinpirole on the odor detection performance of rats before and after spiperone administration.

The influence of five doses of the D-2 receptor agonist quinpirole (0.025, 0.05, 0.075, 0.10, and 0.20 mg/kg IP) on the odor detection performance of 21 adult male Long Evans rats was assessed using high precision olfactometry and a go/no-go operant task. Additionally, ten rats were pre-treated with the D-2 receptor antagonist spiperone (0.62 mg/kg IP) and their performance monitored following quinpirole administration. Treatments were administered every third day in a counterbalanced order, with the quinpirole injections occurring 15 min before, and the spiperone injections 35 min before, the 260-trial test sessions. Quinpirole injection resulted in a dose-dependent decrease in odor detection performance, as measured by the percentage of correct trials and by the non-parametric signal detection sensitivity index SI. Prior treatment with spiperone eliminated these effects. Dose-related influences of quinpirole on (a) the average latency to initiate a detection response (i.e., the S + response latency), (b) the total session duration, and (c) the number of aborted trials were also eliminated or greatly attenuated by prior spiperone injection. These results suggest that D-2 receptors may be involved in the modulation of odor detection performance and related behaviors.

Acetates↗
PubMed1992

Effects of chronic antidepressant treatment on dopamine-related [3H]SCH 23390 and [3H]spiperone binding in the rat striatum.

1. The effects of chronic administration of antidepressants on dopamine-related [3H]SCH 23390 and [3H]spiperone binding to rat striatal membranes were assessed. 2. The monoamine oxidase inhibitors phenelzine (5 or 10 mg kg-1/day) and tranylcypromine (1 mg kg-1/day) and the tricyclic desipramine (10 mg kg-1/day) were administered for 28 days by constant subcutaneous infusion using Alzet (2ML4) osmotic minipumps. 3. These treatments did not alter Kd estimates for either [3H]SCH 23390 or [3H]spiperone binding sites. The monoamine oxidase inhibitors induced a decrease in the Bmax values for both [3H]SCH 23990 and [3H]spiperone binding sites. Desipramine induced a decrease in the Bmax value for [3H]SCH 23390 binding but had no effect on the Bmax value for [3H]spiperone binding.

Animals↗
PubMed1981

[3H]Spiperone binding sites in brain: autoradiographic localization of multiple receptors.

[3H]Spiperone ([3H]SP) binding sites were localized by light microscopic autoradiography, after in vitro labeling. The kinetic and pharmacological characteristics of these binding sites were studied in slide-mounted sections of rat forebrain, and optimal labeling conditions were defined. Autoradiograms were obtained by apposing emulsion-coated coverslips to labeled sections. Differential drug sensitivity allowed the selective displacement of [3H]SP from dopamine receptors by ADTN, from serotonin receptors by cinanserin, from both by haloperidol and from unique spiperone sites by unlabeled spiperone. The various sites presented a differential anatomical localization. For example, only dopaminergic sites were found in the glomerular layer of the olfactory bulb; only serotonergic sites were found in lamina IV of the neocortex, and a high concentration of unique spiperone sites was found in parts of the hippocampus.

Animals↗
PubMed1994

In vivo treatment with mu and delta, but not kappa-selective opioid agonists reduces [3H]spiperone binding to the guinea-pig striatum: autoradiographic evidence.

In guinea-pigs, acute treatment with mu and delta receptor opioid agonists induces sedation and immobility [1,5], and attenuates the behavioural activation produced by the dopamine D2 agonist quinpirole [5]. In contrast, kappa-selective opioid agonists induce dystonic-like movements [4,5,8]. This has led us to investigate the possibility of an interaction between acute opioid treatment and the dopamine D2 system. The effect of acute treatment with mu, delta and kappa opioid agonists on [3H]spiperone binding sites (dopamine D2) in guinea-pig brain was studied using receptor autoradiography. The mu preferring agonist morphine (15 mg/kg subcutaneously, SC) given for 2 h, and the delta receptor selective agonist DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen) (20 nM, intracerebroventricularly, ICV) given for 0.5 h, both decreased the density of specific (butaclamol displaceable) [3H]spiperone binding in the caudate putamen by 23.8 +/- 1.7% and 24.2 +/- 2.7% respectively, and in nucleus accumbens by 26.1 +/- 2.7% and 21.9 +/- 4.6% respectively compared to saline treated animals. There were no significant changes in the level of [3H]spiperone binding to other brain regions examined including frontal cortex, hippocampus, substantia nigra, ventral tegmental area, amygdala, hypothalamic nuclei and cerebellum. In other experiments, incubation of coronal slices from various brain regions with [3H]spiperone, in the presence of a high concentration of morphine (20 microM) or DPDPE (10 microM) did not affect the level of binding, thus precluding effects due to residual tissue levels of drugs after in vivo treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗