Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3,4-Dihydroxy-5-fluorophenylalanine, fluorodopa, was injected into rats in which unilateral lesions of the nigrostriatal pathway had been made. The rats rotated towards the side with the lesions, thus providing further evidence that fluoro-dopa is an analogue of dopa. [(18)F]Fluoro-dopa was then injected intravenously into fully conscious baboons. A well-collimated scintillation detector, aligned along the occipitomental axis, recorded the accumulation of (18)F in the brain. Control animals accumulated (18)F continuously for 100 min. This accumulation represents net transport of [(18)F]fluoro-dopa from blood to brain, decarboxylation to [(18)F]fluoro-dopamine, storage, and degradation of [(18)F]fluoro-dopamine. alpha-Methyl-dopa, a competitive inhibitor of dopa transport and decarboxylation, prevented the accumulation of (18)F; reserpine, known to release stored intracerebral dopamine, discharged (18)F; pargyline, a monoamine oxidase inhibitor, and haloperidol, a known augmentor of intracerebral dopamine turnover, increased the rate of accumulation of (18)F. These changes in the accumulation of intracerebral (18)F, after [(18)F]fluoro-dopa, were commensurate with the known action of the drugs used to induce them and demonstrate the use of a gamma-emitting precursor of a neurotransmitter to monitor simply, atraumatically, and externally the intracerebral metabolism of the transmitter in fully conscious primates. When applied to man, the same technique should be able to provide more conclusive evidence than is presently available for the role of catecholamines in schizophrenia and depression. It should also provide further insight into the natural history of nigrostriatal diseases and the action of drugs used in their treatment.
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PMID:[18F]fluoro-dopa, an analogue of dopa, and its use in direct external measurements of storage, degradation, and turnover of intracerebral dopamine. 41 9

The practice of pharmacotherapy of schizophrenia in Germany is based both on clinical experience and research findings. Experience and studies emphasize that neuroleptic medication is severely limited by side effects including acute extrapyramidal syndromes and tardive dyskinesia. Comparing neuroleptic doses in both acute and maintenance therapy have clinicians encouraged to evaluate methods for treating patients with the lowest effective dose. Other studies have shown that the plasma level may be helpful when deciding which is the best treatment for the illness. More precise results for determining the optimum dose of antipsychotic compounds in the future may be available from positron emission tomography (PET), and from fluorine-magnetic-resonance spectroscopy (FMRS). The management of patients whose illness are refractory to conventional neuroleptics is also discussed. Benzamides and clozapine, both atypical neuroleptics, may be more effective than other available compounds for the severely ill, or for patients who are unable to tolerate the neurological side effects of typical neuroleptics.
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PMID:Pharmacotherapy of schizophrenia in Germany. 135 65

Local cerebral uptake of glucose labelled with fluorine-18 was measured by positron emission tomography in 13 patients with schizophrenia and 37 right-handed volunteers. Patients received no medication for a minimum of 31 days and a mean of 30 weeks. The subjects were administered the labelled deoxyglucose just after the beginning of a 32-minute sequence of blurred numbers as visual stimuli for the Continuous Performance Test. In normal controls, task performance was associated with increases in glucose metabolic rate in the right frontal and right temporoparietal regions; occipital rates were unchanged. Patients with schizophrenia showed both absolutely and relatively reduced metabolic rates in the frontal cortex and in the temporoparietal regions compared with normal controls.
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PMID:Glucose metabolic rate in normals and schizophrenics during the Continuous Performance Test assessed by positron emission tomography. 231 26

Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron emission tomography in 16 patients with schizophrenia and 11 patients with affective disorder. Patients received no medication a minimum of 14 days and an average of 39.8 days. The subjects were administered the deoxyglucose 18F just before receiving a 34-minute 1/s series of unpleasant electrical stimuli to the right forearm while resting with eyes closed in a darkened, acoustically attenuated psychophysiologic testing chamber. Following monitored stimulation in the controlled environment, subjects were scanned and images converted to values of glucose use in micromoles per 100 g per minute according to Sokoloff's model. Data were analyzed with a four-way analysis of variance (ANOVA) with independent groups (normals, schizophrenics, and affectives) and repeated measures for slice level (supraventricular, midventricular, and infraventricular), hemisphere (right, left), and anteroposterior position (four sectors). Both normal subjects and patients showed a significant anteroposterior gradient in glucose use with highest values in the frontmost sector. Patients both with schizophrenia and with affective illness showed less of an anteroposterior gradient especially at superior levels, which was statistically confirmed by ANOVA. Absolute glucose levels in patients, which were actually higher in posterior regions rather than lower in frontal regions, were the largest contributors to the effect. Neither group differences in whole brain glucose use nor left-right asymmetries reached statistical significance. These results are consistent with our earlier reports of a relative hypofrontal function in schizophrenia compared with controls. This report extends this finding to affective illness, sharing a lack of diagnostic specificity with many biologic measures.
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PMID:Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders. 633 2

The neurotransmitter dopamine has biological attributes that make it amenable to study by positron emission tomography, unlike many of the 40 or so neurotransmitters that have been identified in the brain. Dopamine deficiency in the nigrostriatal system is a characteristic of Parkinson's disease, and a disturbance of dopamine metabolism is still widely held to be responsible for the syndrome of schizophrenia. Despite its importance in the regulation of locomotion and mood, it has been impossible to visualize the intracerebral distribution of dopamine and measure its regional metabolism in man. In the first demonstration of the regional distribution of a neurotransmitter in the brain of conscious normal man, we show here that L-3,4-dihydroxyphenylalanine (L-dopa) labelled in the 6-position with the positron-emitting radionuclide fluorine-18, localizes specifically in the dopaminergic pathways of the human brain where its turnover could be measured atraumatically by positron emission tomography.
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PMID:Dopamine visualized in the basal ganglia of living man. 660 27

Two analytical methods for assessing regional glucography with positron emission tomography were compared in 16 patients with schizophrenia and 11 patients with affective disorders. Patients were off all medication a minimum of 14 days and an average of 39.8 days. The subjects were administered fluorine-18-labeled 2-deoxyglucose just before receiving a 34-minute one-per-second series of unpleasant electrical stimuli to their right forearm while resting with their eyes closed in a darkened, acoustically attenuated psychophysiological testing chamber. Following monitored stimulation in the controlled environment, the subjects were scanned and the images were converted to values of glucose use in micromoles per 100 grams per minute, according to Sokoloff's model. Data were analyzed by a four-way analysis of variance (ANOVA) for independent groups (normal subjects, schizophrenic patients, and patients with affective disorders) and for repeated measures of slice level (supraventricular, midventricular , and infraventricular ), hemisphere (right, left), and anteroposterior position (four sectors). Normal individuals and patient groups both showed a significant anteroposterior gradient in glucose use, with the highest values in the sector farthest to the front. Patients with schizophrenia and those with affective illnesses showed less of an anteroposterior gradient than normal individuals, especially at superior levels, which was statistically confirmed by ANOVA. Neither the group differences in whole-brain glucose use nor the left-right asymmetries reached statistical significance. A second technique, involving reconstruction of the lateral cortical surface, also revealed differences between schizophrenics and normal individuals in the superior frontal cortex. These results are consistent with our earlier reports of a relative hypofrontal function in schizophrenia compared with controls; they also extend the finding to the affective illnesses, the other group of major psychoses.
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PMID:Positron emission tomographic image measurement in schizophrenia and affective disorders. 661 Nov 16

Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron-emission tomography in eight patients with schizophrenia who were not receiving medication and in six age-matched normal volunteers. Subjects sat in an acoustically treated, darkened room with eyes closed after injection of 3 to 5 mCi of deoxyglucose 18F. After uptake, seven to eight horizontal brain scans parallel to the canthomeatal line were done. Scans were treated digitally, with a 2.3-cm strip peeled off each slice and ratios to whole-slice activity computed. Patients with schizophrenia showed lower ratios in the frontal cortex, indicating relatively lower glucose use than normal control subjects; this was consistent with previously reported studies of regional cerebral blood flow. Patients also showed diminished ratios for a 2.3-cm square that was positioned over central gray-matter areas on the left but not on the right side. These findings are preliminary; issues of control of mental activity, brain structure identification, and biologic and anatomic heterogeneity of schizophrenia remain to be explored.
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PMID:Cerebral glucography with positron tomography. Use in normal subjects and in patients with schizophrenia. 697 19

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.
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PMID:Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. 1112 99

Considerable efforts have been engaged in the design, synthesis and pharmacological characterization of radioligands for imaging the serotonin transporter, based on its implication in several neuropsychiatric diseases, such as depression, anxiety and schizophrenia. In the 5-halo-6-nitroquipazine series, the fluoro derivative has been designed for positron emission tomography (PET). The corresponding 5-iodo-, 5-bromo- and 5-chloro N-Boc-protected quipazines as labelling precursors, as well as 5-fluoro-6-nitroquipazine as a reference compound have been synthesized. 5-[(18)F]Fluoro-6-nitroquipazine has been radiolabelled with fluorine-18 (positron-emitting isotope, 109.8 min half-life) by nucleophilic aromatic substitution from the corresponding N-Boc protected 5-bromo- and 5-chloro-precursors using K[(18)F]F-K(222) complex in DMSO by conventional heating (145 degrees C, 2 min) or microwave activation (50 W, 30-45 s), followed by removal of the protective group with TFA. Typically, 15-25 mCi (5.5-9.2 GBq) of 5-[(18)F]fluoro-6-nitroquipazine (1-2 Ci/micromol or 37-72 GBq/micromol) could be obtained in 70-80 min starting from a 550-650 mCi (20.3-24.0 GBq) aliquot of a cyclotron [(18)F]F(-) production batch (2.7-3.8% non decay-corrected yield based on the starting [(18)F]fluoride). Ex vivo studies (biodistribution in rat), as well as PET imaging (in monkey) demonstrated that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) readily crossed the blood brain barrier and accumulated in the regions rich in 5-HT transporter (frontal- and posterial cortex, striata). However, the low accumulation of the tracer in the thalamus (rat and monkey) as well as the comparable displacement of the tracer observed with both citalopram, a -HT re-uptake inhibitor and maprotiline, a norepinephrine re-uptake inhibitor (rat), indicate that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) does not have the suggested potential for PET imaging of the serotin transporter (SERT).
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PMID:Synthesis of a fluorine-18-labelled derivative of 6-nitroquipazine, as a radioligand for the in vivo serotonin transporter imaging with PET. 1205 50

Haloperidol decanoate is widely used in the maintenance treatment of schizophrenia and other psychotic disorders, but knowledge concerning its pharmacokinetics at the injected region is very limited. Because the chemical structure of haloperidol contains fluorine, in vivo 19F-magnetic resonance (MR) spectroscopy (repetition time (TR) = 1 s) and chemical shift imaging (CSI; TR = 1 s, pixel size = 15 x 15 mm) were performed in schizophrenic patients who were treated with haloperidol decanoate (three men and one woman) to measure its diachronic change at the injection point and visualize its local distribution after intramuscular injection. 19F signals (T1 time = 365 ms) were obtained at the haloperidol decanoate-injected region. The decrease rate of the signal-to-noise ratio (SNR) by 19F-MR spectroscopy seemed large in comparison with that of the plasma haloperidol concentration. The distribution was clearly visualized by 19F-CSI for a few days after the injection, but after 1 week could no longer be seen. Although the slow-release characteristics of depot neuroleptics have been explained by the slow diffusion of esterified neuroleptics from the oil vehicle, this result may suggest that there are other mechanisms involved in maintaining the plasma haloperidol concentration. In vivo 19F-MR spectroscopy and CSI are potentially applicable for the pharmacokinetic analysis of haloperidol and other drugs containing fluorine in their structure.
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PMID:19F-magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate. 1248 7


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