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PubMed1989

An improved HPLC system for the analysis and purification of organic amine radiopharmaceuticals.

This paper describes the separation of lipophilic amine radiopharmaceuticals on normal phase silica using a reversed phase type eluant. This class of compound usually gives very poor peak symmetry on reversed phase columns. However, excellent separation of a number of amines of interest to Positron Emission Tomography, such as spiperone and its derivatives, has been achieved on this system.

Benzazepines↗
PubMed1990

Labelled agents for PET studies of the dopaminergic system--some quality assurance methods, experience and issues.

Practical methods are described for the quality assurance of three labelled agents (L-6-[18F]fluoro-DOPA, S-[N-methyl-11C]nomifensine and [O-methyl-11C]raclopride) now produced regularly for PET studies of the dopaminergic system in man. These include indirect methods for the initial determination of label position (e.g. 13C-NMR spectroscopy) and also direct methods for the assessment of chiral purity (TLC and HPLC) and the routine determination of radiochemical purity, chemical purity and specific activity (HPLC). Mass spectrometry has been used to identify some impurities. L-6-hydroxy-DOPA (a precursor in vivo of the neurotoxin, L-6-hydroxydopamine) has been detected by HPLC in some preparations of L-6-[18F]fluoro-DOPA. Formulated S-[N-methyl-11C]nomifensine has been found to decrease in radiochemical purity with storage, whereas formulated [O-methyl-11C]raclopride has been found to be stable. Some quality assurance issues are discussed in relation to experience in the application of the described methods and the obtained results.

Carbon Radioisotopes↗
PubMed1990

Carbon-11 labelling of eticlopride in two different positions--a selective high-affinity ligand for the study of dopamine D-2 receptors using PET.

A new highly selective high-affinity dopamine D-2 receptor antagonist, eticlopride ((-)-(S)-5-chloro-3-ethyl-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxysalicylamide), was labelled with 11C in two different positions ([N-ethyl-11C]eticlopride (I)) and ([methyl-11C]eticlopride (II)). Product I was prepared by N-alkylation of the N-desethyl compound with [11C]ethyl iodide. II was prepared by O-alkylation of the diphenolic precursor with [11C]methyl iodide followed by separation of the two methylated products. The radiochemical yields were 15-20% (EOB) with an overall synthesis time of 45-60 min. Both compounds were isolated by semi-preparative HPLC and the radiochemical purity was in both cases greater than 99%. I was injected i.v. in a Cynomolgus monkey and brain radioactivity was measured by positron emission tomography (PET). The specific activity was 70 Ci/mmol at time of injection. There was a marked accumulation of radioactivity in the basal ganglia, regions known to have a high density of dopamine D-2 receptors.

Animals↗
PubMed1996

Do D1/D2 interactions regulate prepulse inhibition in rats?

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is reduced in schizophrenia patients and in dopamine (DA)-activated rats. We previously found that PPI is disrupted by systemic administration of the D2 agonist quinpirole, but not by the D1 agonist SKF 38393. In this report we further characterize the D1 and D2 substrates and their potential interactions in the regulation of PPI in rats. PPI is reduced by concomitant administration of the D1 agonist SKF 38393 (5 mg/kg; relative affinity D1:D2 = 50:1) and by a subthreshold dose (0.1 mg/kg) of the D2 agonist quinpirole, but not by either drug given alone at these doses. Pretreatment with the D2 antagonist raclopride (0.05 mg/kg), but not the D1 antagonist SCH 23390 (0.05 mg/kg), blocks the SKF 38393/quinpirole synergistic reduction of PPI. The relative D1 agonist SKF 82958 (5 mg/kg; relative affinity D1:D2 = 10:1) disrupts PPI, and this effect of SKF 82958 is reversed by the D2 antagonist raclopride but not by the D1 antagonist SCH 23390. Consistent with a recent report (Hoffman and Donovan 1994), the PPI-disruptive effects of the D1/D2 agonist apomorphine (0.5 mg/kg) could be blocked by pretreatment with the D1 antagonist SCH 23390. Surprisingly the PPI-disruptive effects of quinpirole are also opposed by pretreatment with SCH 23390. Our present findings confirm that D2 receptors are important for the regulation of PPI in rats, but they also suggest that there exists a synergistic interaction between D1 and D2 substrates in the regulation of PPI. D1 receptors might modulate PPI in a "rate-dependent" manner in which tonic D1 activity is essential for the full manifestation of the D2-mediated modulation of PPI. However, D1 receptors do not appear to participate in the modulatory mechanisms of sensorimotor gating as an independent substrate.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Inverse agonism at dopamine D2 receptors. Haloperidol-induced prolactin release from GH4C1 cells transfected with the human D2 receptor is antagonized by R(-)-n-propylnorapomorphine, raclopride, and phenoxybenzamine.

Our earlier observation that the antipsychotic drug haloperidol in the absence of dopamine increases cAMP formation and prolactin release in two prolactin-producing cell lines expressing rat dopamine D2 receptors (GH3, GH4ZR7), but not in similar cells devoid of D2 receptors (GH4C1), prompted us to suggest that haloperidol may act as an inverse (or negative) agonist, rather than as a neutral antagonist, at the D2 receptor (Nilsson and Eriksson 1993). In the present study it is shown that haloperidol elicits a dose-dependent increase in prolactin release also in prolactin-producing GH4C1 cells transfected with the human dopamine D2 receptor (short isoform) (GH4C1-hD2s); in addition, it is shown that another antipsychotic drug, flupenthixol, also causes prolactin release per se in this cell line. The effect of haloperidol on prolactin release in GH4C1-hD2s is calcium dependent and counteracted by pretreatment either with the D2 receptor agonist R(-)-n-propylnorapomorphine or with a D2 receptor antagonist that does not affect prolactin release per se (raclopride). In addition, pretreatment with the alkylating compound phenoxybenzamine at a concentration causing a marked reduction of D2 receptor density in GH4C1-hD2s cells significantly counteracted haloperidol-induced prolactin release.

Animals↗
PubMed1990

Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy.

Dopamine receptor selectivity was investigated for a number of dopamine receptor agonists. In vitro, the benzazepine derivatives, e.g., SKF 38393 and SKF 75670 as well as the isoquinoline derivatives, SKF 89626 and SKF 89615, were D1 receptor-selective. All other compounds like apomorphine, CY 208-243, 6,7-ADTN and 3-PPP were either D2-selective or did not discriminate between subtypes. In general, the same receptor profile seen in vitro was observed in vivo. The exceptions to this pattern were: compounds which did not cross the blood-brain barrier, like 6,7-ADTN and SKF 89626, and compounds which appeared nonselective in vitro but demonstrated D2 selectivity in vivo like apomorphine, CI 201-678 and CY 208-243. A number of compounds were characterized in detail with respect to a GTP-induced affinity shift in inhibition of [3H]SCH 23390 binding, and potency and efficacy in stimulating adenylate cyclase from rat striatum. Inhibition of specific [3H]SCH 23390 binding by these agonists in the absence of GTP occurred with Hill slopes below unity and could best be explained by a two-site model with a high (KH)- and low-affinity (KL) component. Inhibition of [3H]SCH 23390 binding in the presence of 15 microM GTP occurred with Hill slopes of unity. The KI values obtained in the presence of 15 microM GTP were similar to the KL values, the low-affinity component observed in the absence of GTP. The capability of the agonists to stimulate the adenylate cyclase was analyzed in relation to dopamine (efficacy = 100%). The efficacy of the benzazepine derivatives varied from 24 (SKF 75670) to 100% (SKF 83189), dependent on the substituents on the benzazepine core. The isoquinolines, SKF 89626 and SKF 89615 had full efficacy, whereas most other agonists tested appeared to have only partial efficacy. In summary, the present paper presents data on dopamine receptor selectivity and efficacy in stimulating adenylate cyclase for a number of dopaminergic agonists. These data may create a basis for selection of agonists in future characterizations of dopaminergic-mediated events.

Adenosine Triphosphate↗
PubMed1992

The cloned dopamine D2 receptor reveals different densities for dopamine receptor antagonist ligands. Implications for human brain positron emission tomography.

Since [3H]emonapride ([3H]YM-09151-2), a benzamide neuroleptic, consistently detects more dopamine D2 receptors than [3H]spiperone in the same tissue, we tested whether this property was inherent in the cloned dopamine D2 receptor. We found that the density of dopamine D2 receptors labelled by [3H]emonapride was 1.5-fold to 2-fold (mean of 1.8-fold) higher than the density of dopamine D2 receptors labelled by [3H]spiperone in cells expressing cloned dopamine D2 receptors (either the short form (from rat) or the long form (from human)), matching similar findings in anterior pituitary tissue (rat or pig) or in post-mortem human caudate nucleus tissue. The situation was similar for another benzamide, [3H]raclopride, which revealed 1.3-fold to 1.8-fold (mean of 1.5-fold) more binding sites than that for [3H]spiperone in cell membranes containing cloned dopamine D2 receptors. The apparently different dopamine D2 receptor densities revealed by these two types of 3H-ligands (i.e. [3H]spiperone and the [3H]benzamides), therefore, arise from an inherent property of the dopamine D2 receptor protein. These findings for the cloned dopamine D2 receptor, therefore, partly explain the higher dopamine D2 receptor density measured in human brain (by positron emission tomography) when using radioactive raclopride compared to results using radioactive methylspiperone.(ABSTRACT TRUNCATED AT 250 WORDS)

Antipsychotic Agents↗
PubMed1992

Site-directed mutagenesis of the human dopamine D2 receptor.

Based on amino acid sequence and computer modeling, two conflicting three-dimensional models of the dopamine D2 receptor have been proposed. One model (Dahl et al., 1991, Proc. Natl. Acad. Sci. USA 88, 8111) suggests that dopamine interacts with aspartate 80 of transmembrane (TM) 2 and asparagine 390 of TM6 with the transmembranes arranged in a clockwise manner, while a second model (Hibert et al., 1991, Mol. Pharmacol. 40, 8) suggests that dopamine interacts with aspartate 114 of TM3 and the serines of TM5 (194 and 197) with the transmembranes arranged in a counterclockwise manner when viewed from the extracellular space. The present study tests the latter model by selectively mutating aspartate 114 and serines 194 and 197 of the human dopamine D2 receptor by site-directed mutagenesis. In addition, two methionines (116 and 117) were mutated to evaluate whether residues near aspartate (114) of the dopamine D2 receptor are critical in differentiating dopamine receptor agonists from adrenoceptor agonists. Removal of the negative charge with the mutation of aspartate (114) to either asparagine or glycine led to a total loss of both agonist and antagonist binding. Individual or dual methionine mutations in positions 116 and 117, to make the dopamine D2 binding pocket more closely resemble the beta 2-adrenoceptor, did not result in a change in selectivity toward noradrenergic agonists or antagonists. The serine mutations revealed interesting differences between the dopamine D2 receptor and the adrenoceptors. In particular, serine 197 appeared more important than serine 194 for agonist binding. In addition, the binding of one agonist (N-0437) was unaffected by individual serine mutations, while the binding of some antagonists, such as raclopride and spiperone, was significantly altered. These findings are discussed in relation to ligand structure and their interactions with the putative binding pocket.

Amino Acid Sequence↗
PubMed1992

Subchronic treatment of rats with remoxipride fails to modify sigma binding sites in the brain.

The effects of 14 days' treatment of rats with haloperidol, remoxipride or both combined on the sigma binding sites in whole brain and liver were determined. The compounds were given subcutaneously via osmotic minipumps at a dose of 0.25 mg/rat/day (corresponding to about 1 mg/kg body weight/day at start) for haloperidol and 2.5 mg/rat/day (10 mg/kg/day) for remoxipride hydrochloride. The sigma recognition sites were determined after a washout period of 2 days with the radioligand [3H](+)-N-propyl-3-(3-hydroxyphenyl)piperidine ([3H](+)-3-PPP). It was found that the haloperidol treatment but not the remoxipride treatment decreased the density of the sigma sites in the brain, without any effect on the affinities of the ligands. Haloperidol had no effect on the binding of [3H](+)-3-PPP to the sigma recognition sites in the liver.

Animals↗
PubMed1994

Remoxipride shows low propensity to block functional striatal dopamine D2 receptors in vitro.

The effect of remoxipride ((S)(-)3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzam ide) on dopamine D2 receptor-mediated inhibition of cAMP formation in rat striatal tissues pieces was established together with that of a number of other dopamine D2 receptor antagonists. The action of remoxipride, three other substituted benzamides, (-)-sulpiride, raclopride and NCQ 298 ((S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylam ide mesylate) and haloperidol, a butyrophenone, was studied in the presence of (I) (+/-) SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) hydrochloride (100 microM) plus pergolide (1 microM) or (II) forskolin (1 microM) plus dopamine (100 microM). In addition, four of the metabolites of remoxipride: FLA 797 ((S)-3-bromo-N[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-6- methoxybenzamide), NCR 181 ((S)(-)-5-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-6- methoxybenzamide tartrate), NCQ 436 ((S)(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dihydroxy-2- methoxybenzamide semioxalate) and NCQ 469 ((S)(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-hydroxy-2,6- dimethoxybenzamide hydrochloride), mainly found in rodents, were studied using test system I. The results demonstrate that remoxipride is significantly weaker in blocking functional striatal dopamine D2 receptors than either of the reference compounds studied and three of the four metabolites. The studies also demonstrate that dopamine D1 and D2 receptor interactions at the level of cAMP formation in the striatum are independent of action potentials or Ca2+.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Forskolin-induced up-regulation and functional supersensitivity of dopamine D2long receptors expressed by Ltk- cells.

Mouse fibroblast Ltk- cells, stably expressing the human dopamine D2long receptor, were grown in the presence of forskolin (100 microM) for 4 or 16 h. The 16 h treatment resulted in a significant up-regulation of the dopamine D2long receptors by 43-96% as measured with [3H]raclopride with no change in the Kd value. A significant increase in the maximal inhibition of acute forskolin-stimulated cAMP accumulation by dopamine (0.1 nM-3 microM) was found both at 4 and 16 h. No such D2long-receptor-coupled response to dopamine could be detected in wild-type, untransfected, Ltk- cells with or without forskolin treatment. Furthermore, basal cAMP levels as well as the maximal response to acute forskolin stimulation decreased in the D2long receptor expressing cells with the treatment, by 33% and 23% respectively. The results indicate that persistent maintenance of high cAMP levels in transfected Ltk- cells may lead to adaptive quantitative and functional changes of the dopamine D2long receptor reminiscent of receptor supersensitivity induced by chronic antagonist treatment in vivo where the receptor targeted is inhibitorily coupled to adenylyl cyclase, as is the D2long receptor. This may provide a model for studying mechanisms underlying dopamine D2 receptor up-regulation and receptor supersensitivity, not readily induced in cell lines.

Adenylyl Cyclases↗
PubMed1995

Deriving the therapeutic concentrations for clozapine and haloperidol: the apparent dissociation constant of a neuroleptic at the dopamine D2 or D4 receptor varies with the affinity of the competing radioligand.

The apparent dissociation constant, Ki, for a neuroleptic at the dopamine D2 or D4 receptor was consistently higher when competed against [3H]nemonapride than against [3H]spiperone which was in turn higher than that against [3H]raclopride. This finding obtained for all four types of dopamine receptors studied, including the native dopamine D2 receptor in the anterior pituitary tissue, the human D2long receptor, the human D2short receptor and the human D4.4 receptor. Some neuroleptics revealed a difference of over 10-fold between the Ki using [3H]nemonapride and the Ki using [3H]raclopride. The KD values of the three 3H-ligands and the neuroleptic Ki values were lower when using a much lower concentration of tissue, indicating that depletion of ligand presumably accounted for the phenomenon. The Ki values of each neuroleptic were related to the the tissue/buffer partition coefficients of the three 3H-ligands. Extrapolating the neuroleptic Ki value down to a tissue/buffer partition coefficient of unity or zero led to a Ki value for competition versus a water-soluble ligand such as dopamine. Clozapine extrapolated to a Ki value of 1.3 nM. Direct measurement gave a Ki value of 1.6 nM for [3H]clozapine at the dopamine D4 receptor. When competing versus endogenous dopamine, this clozapine value of 1.6 nM would rise to 20 nM for the blockade of 75% of dopamine D4 receptors, matching the observed therapeutic concentration of 18 nM. These data also explain why clozapine occupies 48% of the D2 receptors in patients when measured with [11C]raclopride, but between 0% and 22% when measured with [18F]methylspiperone or [18F]fluoroethylspiperone.

Animals↗
PubMed1991

A three-year photopatch study in Thailand.

Photopatch testing was performed on 274 patients who had history of photosensitivity at the Institute of Dermatology Thailand from 1987 through 1989. A total of 92 positive photocontact reactions and 71 positive contact reactions were seen. The most frequent positive photopatch test reactions were to sulfanilamide (18.2%) followed by Jadit (4.4%) chlorpromazine (3.6%) promethazine (3.6%) and fenticlor (3.2%). The most common photodermatoses was polymorphous light eruption (60.9%). Photocontact dermatitis was established in 28 patients (10.2%) while other skin diseases aggravated by sunlight were seen in 47 patients (17.2%).

4-Aminobenzoic Acid↗
PubMed1993

Enhancement of the opiate withdrawal response by antipsychotic drugs in guinea-pigs is not mediated by sigma binding sites.

Haloperidol, a 'typical' neuroleptic, with affinity for both dopamine (DA) receptors and sigma binding sites, exacerbates morphine withdrawal in guinea-pigs. In this study, the effects of sigma ligands (+)- and (-)-SKF 10,047 (1 and 10 mg/kg s.c.), pentazocine (20 mg/kg s.c.) and DTG (1 and 10 mg/kg s.c.), non-competitive NMDA antagonists ketamine hydrochloride (20 mg/kg s.c.) and MK-801 (0.025, 0.1 and 1 mg/kg s.c.), 'atypical' neuroleptic drugs with (remoxipride 25 mg/kg s.c.) and without (raclopride 10 mg/kg s.c.; clozapine 25 mg/kg s.c.) affinity for sigma sites, and atropine sulphate (20 mg/kg s.c.), were investigated on the opiate withdrawal response induced by naloxone hydrochloride (15 mg/kg s.c.) in guinea-pigs treated 2 h before with a single dose of morphine sulphate (15 mg/kg s.c.). (+)- and (-)-SKF 10,047, pentazocine, ketamine and MK-801, given 0.5 h before naloxone, significantly attenuated the increased locomotor activity and other behaviours associated with morphine withdrawal in guinea-pigs. The selective sigma ligand DTG, and remoxipride had no effect on the withdrawal response but raclopride, clozapine, and atropine exacerbated the response. It is concluded that exacerbation of the morphine withdrawal response by neuroleptics is not related to sigma activity but to other mechanisms. Furthermore NMDA but not sigma mechanisms might play a role in the morphine withdrawal response.

Analysis of Variance↗
PubMed1996

Measuring age-related changes in dopamine D2 receptors with 11C-raclopride and 18F-N-methylspiroperidol.

This study investigates the rate of age-related dopamine D2 receptor loss as determined by positron emission tomography (PET) and 11C-raclopride and compares it with D2 loss previously estimated with 18F-N-methylspiroperidol (NMS). Dopamine D2 receptors were measured with 11C-raclopride in 24 healthy volunteers (24-73 years of age) using the ratio of the distribution volume in striatum to that in cerebellum (Bmax/Kd + 1). The results were compared with those obtained in 20 healthy male volunteers (20-49 years of age) in whom D2 receptors were measured with NMS using the ratio index (slope of the striatum-to-cerebellum ratio as a function of time). Findings of correlational analysis between age and dopamine D2 receptor availability were significant for both ligands. Estimates of dopamine D2 receptor loss per decade corresponded to 7.9% for the 11C-raclopride study and 7.8% for the NMS study. Both ligands documented significant age-related decreases in dopamine D2 receptors that occurred relatively early in life (40 years of age).

Adult↗
PubMed1996

Test-retest reliability of central [11C]raclopride binding at high D2 receptor occupancy. A PET study in haloperidol-treated patients.

Central D2 dopamine receptor occupancy may be a useful measure to establish clinical guidelines for optimal antipsychotic drug treatment. The use of positron emission tomography (PET) to explore quantitative relationships among D2 receptor occupancy and clinical effects depends on the reliability of such measurements. The calculation of D2 receptor occupancy using [11C]raclopride is routinely based on a ratio-equilibrium analysis, in which the ratio of radioactivity concentration in the striatum to that in the cerebellum is determined. To examine the reliability of such ratios, a test-retest analysis was performed in four schizophrenic patients treated with haloperidol decanoate. PET experiments with [11C]raclopride were repeated in each subject during the same day. The putamen to cerebellum ratio (P/C ratio) ranged from 1.44 to 1.07 among the four patients, corresponding to a D2 receptor occupancy of 62 to 71%. In each subject, the P/C ratios remained highly similar, with quotients 0.98, 1.01, 1.04 and 1.06 between the two experiments. The high test-retest reproducibility of the P/C ratios indicates that measurements of D2 receptor occupancy with the present methods are highly reliable, and support the further use of PET to optimize the drug treatment of schizophrenia.

Adult↗
PubMed1993

Synthesis and in vivo distribution in the rat of a dopamine agonist: N-([11C]methyl)norapomorphine.

A method for the rapid production and purification of 10,11-dihydroxy-N-([11C]methyl)norapomorphine ([11C]APO), a dopamine agonist (DA), is described. The potency of this ligand for studying the D2-receptors was examined. The label was introduced by N-methylation of norapomorphine hydrobromide with no-carrier-added (n.c.a) [11C]CH3I, produced from cyclotron-produced [11C]carbon dioxide. In 60 min (EOB) a radiochemical yield of 15% (corrected for decay) was achieved, based on [11C]CH3I. The specific activity ranged from 5 to 11 GBq/mumol. The distribution, after intravenous injection, was studied in rats. The radioactivity level in the striatum was higher than in the cerebellum and frontal cortex and was decreased after D2-blockade. The highest uptake ratio (1.47) was found at 30 min after injection. Dopamine depletion with reserpine did increase the striatum/cerebellum ratio at a low dosage of [11C]APO (10 nmol/kg). High uptakes of [11C]apomorphine were found in the lungs, liver and kidneys.

Animals↗