Butyrophenone Neuroleptics Research Articles

Safety of Haloperidol and Penfluridol in Pregnancy

To assess the safety of the butyrophenone neuroleptics haloperidol and penfluridol in pregnancy. The rate of major anomalies was compared between a cohort of pregnant women counseled for gestational exposure to haloperidol or penfluridol and a control group counseled for nonteratogen exposure. This multicenter, prospective, controlled study was conducted within the European Network of Teratology Information Services (ENTIS) and included women who contacted 1 of 4 teratology information services for counseling between January 1989 and December 2001. We followed up on the outcomes of 215 pregnancies exposed to haloperidol (N = 188) or penfluridol (N = 27)-78.2% (of 206) were in the first trimester-and compared to outcomes of 631 ENTIS controls. The rate of congenital anomalies did not differ between the haloperidol/penfluridol-exposed group and the control group (6/179 = 3.4% vs. 22/581 = 3.8%, p = .787). No difference was found by limiting the analysis to those exposed to butyrophenones during the first trimester. There were 2 cases of limb defects in the butyrophenone-exposed group (1 after haloperidol and 1 after penfluridol exposure) and none in the controls. A higher rate of elective terminations of pregnancy (8.8% vs. 3.8%, p = .004), a higher rate of preterm birth (13.9% vs. 6.9%, p = .006), a lower median birth weight (3155 g vs. 3370 g, p < .001), and a lower median birth weight of full-term infants (3250 g vs. 3415 g, p = .004) were found in the butyrophenone-exposed group compared to the controls. This study suggests that haloperidol and penfluridol do not represent a major teratogenic risk. Since a possible association between butyrophenone exposure and limb defects cannot be ruled out with this sample size, a level II ultrasound with emphasis on the limbs should be considered in pregnancies with first trimester exposure.

Rapid and Efficient Synthesis of High-Purity Fluorine-18 Labeled Haloperidol and Spiperone via the Nitro Precursor in Combination with a New HPLC Separation Method

Abstract We have completed a convenient synthesis of fluorine-18 labeled butyrophenone neuroleptics from their nitro precursors. Thus, we have developed an efficient single-column HPLC system using a C18-bonded vinyl alcohol copolymer gel (octadecyl polymer, ODP) column and strongly alkaline solvent systems for purifying of the 18F-labeled butyrophenone neuroleptics obtained by a single-step 18F-for-nitro exchange reaction. The method has been applied to the synthesis of two typical butyrophenone neuroleptics ([18F]haloperidol and [18F]spiperone) with high purity in high yield. With information concerning the optimized conditions for the 18F-for-nitro exchange reaction, the synthetic method would be useful for synthesizing various 18F-labeled compounds.

DELIRIUM: Advances in Diagnosis, Pathophysiology, and Treatment

This article discusses research in the areas of morbidity and mortality, epidemiologic risk factors, phenomenology, pathophysiology, and treatment of delirium. Delirium assessment instruments are reviewed. The neuropathophysiologic understanding of delirium is discussed in the context of important CNS neural circuitry. Pharmacologic treatments of delirium in adults and children are outlined, with particular emphasis on intravenous use of butyrophenone neuroleptics.

Remote controlled one-step production of 18F labeled butyrophenone neuroleptics exemplified by the synthesis of n.c.a. [ 18F] N-methylspiperone

A remote controlled synthesis for the routine production of [ 18F]butyrophenones is described. The modular set-up includes a one step HPLC- and a solid phase extraction unit both connected on-line to a single unit reactor. [ 18F]N-methylspiperone was synthesized from 8-[4-(4-nitrophenyl)-4-oxobutyl]-3-methyl-1-phenyl-1,3,8-triazaspiro [4.5]decan-4-one using the direct nucleophilic aromatic fluorination in presence of a cryptate consisting of Kryptofix® 2.2.2, potassium oxalate and a small amount of potassium carbonate (50 μg). The one-step synthesis gave radiochemical yields of 15–20% within a synthesis time of 70 min, including product formation. Starting with the appropriate amount of 18F-fluoride up to 180 mCi [ 18F]MSP have been obtained. The radiochemical purity is in the range of 96–98% and the specific activity is >4000 Ci/mmol. The system is generally useful for the synthesis of other n.c.a. [ 18F]butyrophenone neuroleptics such as [ 18F]N-methylbenperidol starting with the corresponding nitro precursors.

The Rapid Synthesis of High Purity [18F]Butyrophenone Neuroleptics from Nitro Precursors for PET Study

Abstract We have completed rapid syntheses of [18F]butyrophenone neuroleptics ([18F]haloperidol and [18F]spiperone) from their nitro precursors in high radiochemical yields (up to 21%) by combining a one-step nitro-fluoro exchange reaction and a novel high performance liquid chromatography (HPLC) separation method. The synthesis time was ca. 95 min and both the radiochemical and chemical purities of the labeled products were over 99%.

Improvements in the production of fluorine-18 labeled butyrophenone neuroleptic agents

Improvements toward the no-carrier-added (nca) production of [ 18F]-butyrophenone neuroleptics are presented. The preparation of 1-cyclopropylketo 4- N, N, N-trimethylanilinium trifluoromethane sulfonate 2b and its use as a substrate for nca fluorination yielding cyclopropyl 4-[ 18F]fluorophenyl ketone 3 are described. Advantages to the use of the anilinium salt 2b were a higher product yield (67.4%) and cleaner reaction mixture relative to its nitro counterpart 2a (52–59%). The ionic nature of this labeling precursor was expected to afford a final radiopharmaceutical product with a higher effective specific activity than that achieved with 2a. The reaction sequence continues with a novel method for the cleavage of the cyclopropyl moiety using diiodosilane. This reagent was utilized for ring opening of 3 to afford the intermediate product, γ-iodo-4-[ 18F]fluorobutyrophenone 1b, which was produced in high yields (66.7%), short reaction times (3–10 min), using relatively mild reaction conditions (room temperature) which avoided a production of volatile fluorine-18 labeled species. Compound 1b, was in turn utilized as an alkylating agent for the production of [ 18F]spiperone which was produced with a specific activity of 1470 Ci/mmol ( n = 2). The reported methodology lends itself well to applications of other potentially more useful butyrophenone based imaging agents, i.e. N-methylbenperidol.

Optimization studies concerning the direct nucleophilic fluorination of butyrophenone neuroleptics

Based on the direct nucleophilic aromatic substitution described previously for [ 18 F]N- methylspiperone the butyrophenone neuroleptics benperidol, droperidol, fluanisone and haloperidol were labelled with fluorine-18. The n.c.a. aromatic nucleophilic NO 2 → 18F substitution takes place in the presence of the moderately basic cryptate system consisting of Kryptofix® 2.2.2., potassium oxalate and potassium carbonate. The one step labeling reaction was performed in different solvents and is equally successful in dimethylsulfoxide, dimethylformamide or dimethylacetamide yielding 25–35% (EOS) within a reaction time of 5–30 min in the range of 140–160°C at analytical activity levels.

Lactones. 24. "Gamma-lactonized" neuroleptics--synthesis, stereochemistry and affinity at the D2 receptor

Addition of piperidines 15a-d to methylene lactones 8,14a gives the "gamma-lactonized" diphenylbutylpiperidine-type neuroleptics 3a,b,d,4a-d. 8 can be produced by cyclization or--as well as 14--from the corresponding alpha-carboxylactone. 1H- and 13C-nmr data give evidence for the equatorial position of the aminomethyl group in all derivatives of 3 and 4 and bisequatorial-trans-configuration in 4a-d. 3H-spiroperidole displacement at the D2 receptor in rat brain by 3,4 and the "gamma-lactonized" butyrophenone neuroleptics 1,2a-c was investigated. Some compounds show moderate up to high (3b) activity.

Beta-phenylethylamine (PEA): an endogenous anxiogen? three series of experimental data

Like the anxiogenic drugs caffeine, pentylenetetrazole, and yohimbine, the endogenous neuroactive monoamine beta-phenylethylamine (PEA) is effective in three tests for anxiogens in mice. In a social interaction test it reduced both the number and duration of contacts. In a conflict situation test (a dark-light chamber) it reduced the number of transitions between dark and light compartments. Diazepam, a standard anxiolytic, prevented both effects of PEA. Intracerebroventricular administration of PEA induced generalized clonic seizures which were antagonized by various anxiolytics but not by the tested doses of butyrophenone neuroleptics and standard anticonvulsants effective in other tests for convulsants.

Comparison of three 18F-labeled butyrophenone neuroleptic drugs in the baboon using positron emission tomography.

The butyrophenone neuroleptics spiroperidol, benperidol, and haloperidol were radiolabeled with fluorine-18 and studied in baboon brain using positron emission transaxial tomography (PETT). Pretreatment of the baboon with a high pharmacological dose of (+)-butaclamol reduced the specifically bound component of radioactivity distribution in the striatum to approximately the radioactivity distribution found in the cerebellum. Comparative studies of brain distribution kinetics over a 4-h period indicated that either [18F]spiroperidol or [18F]benperidol may be suitable for specific labeling of neuroleptic receptors. In an 8-h study with [18F]spiroperidol, striatal radioactivity did not decline, suggesting that spiroperidol either has a very slow dissociation rate or that it binds irreversibly to these receptors in vivo. [18F]Haloperidol may not be suitable for in vivo PETT studies, because of a relatively high component of nonspecific distribution and a faster dissociation from the receptor. Analysis of 18F in plasma after injection of [18F]spiroperidol indicated rapid metabolism to polar and acidic metabolites, with only 40% of the total radioactivity being present as unchanged drug after 30 min. Analysis of the metabolic stability of the radioactively labeled compound in rat striatum indicated that greater than 95% of [18F]spiroperidol remains unchanged after 4 h.

Sensitive analysis of butyrophenone neuroleptics by high-performance liquid chromatography with ultraviolet detection at 254 nm

Sensitive analysis of butyrophenone neuroleptics by high-performance liquid chromatography with ultraviolet detection at 254 nm

Carrier-added and no-carrier-added syntheses of [ 18F]spiroperidol and [ 18F]haloperidol

Syntheses of [ 18F]haloperidol and [ 18F]spiroperidol in both no-carrier-added and carrier-added forms have been accomplished. The no-carrier-added [ 18F]butyrophenone neuroleptics were prepared in low (<2%) yield by acid decomposition of aryl piperidine triazenes. Carrier-added 18F-neuroleptics were prepared in better (5–17%) yields by 18F-for- 19F nucleophilic aromatic substitution. The preparation of all synthetic precursors, and procedures for radiolabeling are fully described.

Application of the nucleophilic substitution reaction to the synthesis of No‐carrier‐added [18F]fluorobenzene and other 18F‐labeled aryl fluorides

AbstractNo‐carrier‐added (NCA) [18F]fluorobenzene was prepared in a multistep synthesis with a radiochemical yield of 20‐30%.A series of NCA and CA 18F‐labeled aryl fluorides which are important precursors of 18F‐labeled butyrophenone neuroleptics have also been synthesized in radiochemical yields of 30–50%. The direct synthesis of [18F]spiroperidol and [18F]benperidol from the parent compounds and/or nitro and/or chloro compound using the nucleophilic substitution reactions were also investigated.

3H]dopamine labeling of D3 dopaminergic sites in human, rat, and calf brain.

The binding of [3H]dopamine to brain regions of calf, rat, and human was investigated. The calf caudate contained the highest density of [3H]dopamine binding sites, with a Bmax value of 185 fmol/mg protein, whereas rat and human striatum contained one-third this number of sites. The KD values for [3H]dopamine in all tissues were 2-3 nM. Dopaminergic catecholamines (dopamine, apomorphine, 6,7-dihydroxy-2-aminotetralin, and N-propylnorapomorphine) inhibited the binding of [3H]dopamine in all three species, at low concentrations, with IC50 values of 1.5 to 6 nM. Neuroleptics, in contrast, inhibited the binding at high concentrations (with IC50 values of 200 to 40,000 nM). The [3H]dopamine binding sites were saturable, heat-labile, and detectable only in dopamine-rich brain regions; these sites differed from D2 dopamine sites (labeled by [3H]butyrophenone neuroleptics), and from D1 dopamine sites (labeled by [3H]thioxanthene neuroleptics) associated with the dopamine-stimulated adenylate cyclase. We have, therefore, called these high-affinity [3H]dopamine binding sites D3 sites. [3H]Apomorphine and [3H]ADTN also appeared to label D3 sites. These ligands however, were less selective than [3H]dopamine, and labeled sites other than D3 as well. Assay conditions were important in determining the parameters of [3H]dopamine binding. The optimum conditions for selective labeling of the D3 dopaminergic sites, using [3H]dopamine, required the presence of EDTA and ascorbate.

Liquid chromatographic assay of phenothiazine, thioxanthene and butyrophenone neuroleptics and antihistamines in blood and plasma with conventional and radial compression columns and UV and electrochemical detection

An assay strategy for determining a wide range of phenothiazine, thioxanthene and butyrophenone neuroleptics and antihistamines both alone and in combination in blood and plasma is described. The general method employs liquid chromatography with both conventional and radial compression nitrile bonded columns. Detection is by ultraviolet absorption spectrophotometry or by amperometry depending on the concentrations to be measured. Ultraviolet absorption is suitable down to 10 ng/ml. Below this level amperometry is preferable. The various compounds are used as internal standards for each other. The lower limit of detection is approximately 0.1 ng ml −1 with a 10-ml sample. The within-run coefficient of variation is a maximum of 7.3%.

A comparison of the effects of neuroleptics on phencyclidine-induced behaviors in the rat

The dose-response effects of neuroleptic pretreatment on phencyclidine (PCP; 3 or 5 mg/kg)-induced locomotor activity, stereotyped behaviors and ataxia were quantified in groups of male rats using rating scales recently developed in this laboratory. Three butyrophenone neuroleptics consistly produced dose-dependent antagonism of the behavioral effects of PCP administration. Fluphenazine antagonized the behavioral effects produced by 3 mg/kg PCP but not those produced by 5 mg/kg PCP. Each of the other neuroleptics examined (chlorpromazine, thioridazine, mesoridazine, triflupromazine, cis-flupenthixol) had no consistent antagonistic effect or actually enhanced one or more of the behavioral effects of PCP. Some neuroleptics slightly reduced PCP locomotion or stereotypies at high doses, but these effects were probably a non-specific consequence of the synergistic ataxia-producing properties of these drugs. In a second set of experiments, atropine sulfate pretreatment increased PCP-induced locomotor activity and stereotyped behaviors but had no effect on ataxia; pretreatment with physostigmine produced opposite effects. Combined pretreatment with haloperidol and atropine sulfate significantly reduced only haloperidol antagonism of PCP-induced ataxia, thus suggesting that non-dopaminergic effects of neuroleptics may interfere with their ability to antagonize PCP.

A comparison of butyrophenone and tricyclic neuroleptics with narcotics in blocking withdrawal signs in rats continuously infused with morphine

AbstractNarcotic dependence was established in male rats by continuous infusion of morphine given in increasing concentrations. Termination of the morphine infusion resulted in the reliable occurrence of body shakes. Narcotic drugs, morphine, fentanyl, and methadone, blocked withdrawal body shakes in a dose‐dependent manner. The butyrophenone neuroleptics, haloperidol, benperidol, and azaperone, were also effective in reducing withdrawal body shakes at doses that do not produce side effects. Trifluoperazine and chlorpromazine, two tricyclic neuroleptics were effective in reducing withdrawal shakes only at high doses that produced side effects. The anti‐withdrawal action of morphine, haloperidol, benperidol, and azaperone but not of chlorpromazine and trifluoperazine was antagonized by naloxone.

Determination of haloperidol in human serum by radioimmunoassay.

A radioimmunoassay has been developed which enables accurate determination of haloperidol in human serum. Antiserum was prepared by immunizing guinea pigs with haloperidol (O-carboxymethyl)oxime derivative (III) coupled with bovine serum albumin. With the antiserum, 3H-haloperidol and dextran-coated charcoal, the assay of haloperidol in serum was possible over a concentration range of 1 to 50 ng/ml, using 0.1 ml of human serum without the need of an extraction procedure. Data obtained by radioimmunoassay are in good agreement with those obtained by gas chromatography. No appreciable cross-reactivity was observed neither with haloperidol metabolites nor with other butyrophenone neuroleptics. Serum levels of haloperidol in schizophrenic patients receiving single oral dosing (6 mg/subject) have also been determined.

Reduction of the hypotensive effect of clonidine and alpha-methyldopa by various psychotropic drugs.

1. In chloralose-anaesthetized cats the centrally induced hypotensive effect of clonidine, and in some cases alpha-methyldopa, was diminished by pretreatment with a variety of tricyclic antidepressants and neuroleptic agents. 2. The interaction is assumed to occur at the central alpha-adrenoreceptors. Clonidine or alpha-methyl-noradrenaline (from alpha-methyldopa) are the agonists, and the aforementioned psychotropic drugs are the antagonists. 3. Psychotropic drugs which are not alpha-receptor blockers, like butyrophenone neuroleptics (pimozide and haloperidol) or benzodiazepine tranquillizers, do not significantly diminsh the centrally induced hypotensive effect of clonidine.

Inhibition of cholinesterase and acetylcholin-esterase in vitro by butyrophenone neuroleptics

The inhibitory effect of six butyrophenone neuroleptics: haloperidol, triperidol, moperone, floropipamide, benperidol and droperidol on the activity of partially purified aspecific horse serum ChE and on purified Electrophorus electricus specific AChE was studied with AThCh as substrate using Ellman's spectrophotometric method. All butyrophenones were found to be inhibitors of ChE, the K i being in the range 10 −5 M and all followed a fully competitive type of inhibition. There were small differences in K i -values among various butyrophenones, while there were great differences in K i -values between the butyrophenones, the two phenothiazines and imipramine, the last three drugs being far more potent competitive ChE inhibitors ( K i 10 −6–10 −7 M) than the butyrophenones. All the butyrophenones were also found to inhibit AChE, the overall inhibitor constants being in the range 10 −4 to 10 −5 M and all showed a mixed type of inhibition. The most potent of the butyrophenones are droperidol and benperidol, the benzimidazolone derivatives. There are no great differences in the K i -values for the butyrophenones, the two phenothiazines and imipramine for inhibition of AChE.