5-[I-125/123]lodo-3(2(S)-azetidinylmethoxy)pyridine, a radioiodinated analog of A-85380 for in vivo studies of central nicotinic acetylcholine receptors

The in vivo biodistribution profile of the novel nicotinic acetylcholine receptor (nAChR) radioligand 5-[I-125/123]Iodo-3(2(S)-azetidinylmethoxy)pyridine, [I-125/123]-5-IA, in mouse brain was examined. This radiotracer displayed good brain penetration (3.1% of the injected dose (ID) in whole brain at 15 min post-radioligand injection). Radioligand distribution was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus (14.9 %ID/g at 60 min), moderate uptake in cortex (8.5 %ID/g at 60 min), and lowest uptake in the cerebellum (2.4 %ID/g at 60 min). Pretreatment with several different nAChR agonists (A-85380, (-)-nicotine, cytisine) significantly inhibited [I-125]-5-IA binding in all brain regions studied (P < 0.01) demonstrating the high specificity of the radioligand for nAChRs. Blocking doses of the muscarinic antagonist scopolamine and the non-competitive nAChR channel blocker mecamylamine had no significant effect on radioactive uptake supporting the in vitro selectivity of [I-125]-5-IA for the nAChR component of the cholinergic system. [I-125]-5-IA binding sites were shown to be saturable with unlabeled 5-IA. With a relatively low acute toxicity (LD50 > 3 mg/kg via intravenous injection in mice) and high in vivo specificity and selectivity, 5-IA labeled with the imaging radionuclide I-123 may prove useful for single photon emission computed tomography (SPECT) studies of nAChRs in human subjects.     

Decreased benzodiazepine receptor binding in Machado-Joseph disease

Benzodiazepine receptor binding was assessed in four Japanese men with Machado-Joseph disease. METHODS: The distribution of benzodiazepine receptors was measured by radionuclide imaging (SPECT) after intravenous administration of 123I-iomazenil (Ro 16-0154). RESULTS: SPECT demonstrated decreased binding throughout the cerebral cortex and cerebellum in all patients. Binding potential (receptor concentration x affinity) was diffusely decreased in cerebral cortex, thalamus, striatum and cerebellum compared with control subjects, suggesting that GABAergic function may be decreased globally in these patients. Cerebral blood flow was largely normal, and no cerebral cortical atrophy was evident on MRI. CONCLUSION: Iodine-123-iomazenil SPECT may become a potent method for detecting impairment of the cerebral cortex even before brain perfusion SPECT or MRI can reveal early abnormalities.     

Up-regulation of estrogen receptor mRNA and estrogen receptor activity by estradiol in liver of rainbow trout and other teleostean fish

[125I]- and [123I]NNC 13-8241 were prepared from the trimethyltin precursor and radioactive iodide using the chloramine-T method. The total radiochemical yields of [125I]- and [123I]NNC 13-8241 were 60-70% and 40-50% respectively, with radiochemical purity higher than 98%. In binding studies with [125I]NNC 13-8241 in rats in vitro and in vivo a high uptake of radioactivity was demonstrated in brain regions known to have a high density of benzodiazepine (BZ) receptors such as the occipital and frontal cortex. SPECT examination with [123I]NNC 13-8241 in a Cynomolgus monkey demonstrated a high uptake of radioactivity in the occipital and frontal cortex. After displacement with flumazenil radioactivity in these brain regions was reduced to the level of a central region including the pons. Four hours after injection about 80% of the radioactivity in monkey plasma represented unchanged radioligand. This low degree of metabolism indicates that NNC 13-8241 is metabolically more stable than the radioligands hitherto developed for imaging of BZ-receptors in the primate brain.     

Autolysis of Lactococcus lactis ssp. lactis and Lactobacillus casei ssp. casei. Cell lysis induced by a crude bacteriocin

Clinical studies indicate that patients with acute schizophrenia may benefit from benzodiazepine treatment. Therefore we investigated the benzodiazepine receptor distribution and diazepam binding in 20 patients with DSM-III schizophrenia using single photon emission computed tomography (SPECT) with iomazenil as the ligand. In each patient, two SPECT images were obtained: SPECT 1 was obtained 2 h after intravenous injection of 200 MBq I-123-iomazenil. Following SPECT 1, patients received 10 mg diazepam intravenously. Twenty min later, SPECT 2 was started. The highest iomazenil uptake was found in the occipital cortex followed by the frontal and temporal cortices. Baseline iomazenil uptake in the medial frontal cortex was significantly (P < 0.05) correlated with the BPRS total score (r = 0.46). Diazepam injection led to a significant activity decrease in iomazenil binding which was greatest in the frontal regions of interest. With respect to the medial frontal cortex, this effect was significantly (P < 0.05) more pronounced in patients with a remitting than a chronic course of the disorder. These findings suggest that changes of the benzodiazepine receptor system in the frontal cortex may be associated with severity and chronicity of schizophrenia.     

In vitro and in vivo characterization of R(+)-FIDA2: a dopamine D2-like imaging agent

R(+)-FIDA2, (R)-(+)-2,3-dimethoxy-5-iodo-N-[(1-(4'-fluorobenzyl)-2-pyrrolid iny l)- methyl]benzamide, is a new dopamine D2-like receptor imaging agent that can be labeled with either 123I or 18F for SPECT or PET imaging. The purpose of this study was to characterize its in vitro and in vivo binding properties. METHODS: In vitro binding studies using [125I]R(+)-FIDA2 were performed in Sf9 cells expressing dopamine D2 or D3 receptors and in rat basal forebrain homogenates, which contain a high density of dopamine D2-like receptors. A series of in vivo SPECT imaging studies in nonhuman primates (cynomologous monkeys) were performed by intravenously injecting 7.1 +/- 1.0 mCi of [123I]R(+)-FIDA2. At least one control study and one displacement experiment, in which a cold compound was injected intravenously 90 min after tracer injection, was performed in each monkey. Data were acquired in 10-min frames for 180 min, and the activity in regions of interest (basal ganglia and cerebellum) were plotted versus time. RESULTS: Iodine-125-R(+)-FIDA2 displayed Kd values for D2 and D3 receptor subtypes expressed in Sf9 cells of 0.11 and 0.04 nM, respectively. As expected, SPECT images of monkey brain (transaxial sections, 2 mm) showed that the radioactivity was localized in the area of the basal ganglia and reached peak concentrations in 11.5 +/- 5.8 min postinjection. An injection of R(+)7-OH-PIPAT, a new ligand that is selective for dopamine D3 receptors and the high affinity state of dopamine D2 receptors, did not show significant displacement of [123I]R(+)-FIDA2 binding in the basal ganglia. CONCLUSION: These studies indicate that R(+)-FIDA2 may be a useful ligand for in vitro pharmacological characterization and in vivo imaging of CNS dopamine D2-like receptors.     

Pharmacological evaluation of [11C]A-84543: an enantioselective ligand for in vivo studies of neuronal nicotinic acetylcholine receptors

[11C]A-84543, 3-[(1-[11C]methyl-2(S)-pyrrolidinyl)methoxy]pyridine, is a specific and enantioselective neuronal nicotinic acetylcholine receptor (nAChR) radiotracer. The in vivo biodistribution of this radiotracer in mice showed high brain uptake and a distribution consistent with the density of nAChRs. Highest uptake was observed in the thalamus (9.6 %ID/g), cortex (9.9 %ID/g), superior colliculus (7.6 %ID/g) and hippocampus (7.6 %ID/g) at 5 min followed by clearance. As a measure of specificity, the thalamus/cerebellar ratio reached a maximum of 2.3 at 30 min post-injection. Radioactivity in the thalamus and superior colliculus was reduced by 33% by pre-administration of unlabeled A-84543. The nAChR agonists (-)nicotine, cytisine, and (+) epibatidine reduced the radioactivity due to [11C]A-84543 in the superior colliculus by 41%, 38%, and 27%, respectively, while lobeline, which also interacts with central nAChRs, produced a 24% inhibition. The noncompetitive nAChR ligand, mecamylamine displayed no inhibitory effect on [11C]A-84543 accumulation in any brain region. Ketanserin (5-HT2/5-HT2C), scopolamine (mAChR antagonist), (+)butaclamol (DA receptor antagonist), and haloperidol (D2/sigma) also displayed no inhibitory effect in any brain region studied. With the pharmacologically less active enantiomer, 3-[(1-[11C]methyl-2(R)-pyrrolidinyl)methoxy] pyridine, high brain uptake was also observed, but with a low thalamus/cerebellar ratio of 1.4 at 30 min post-injection. [11C]A-84543 displays enantioselectivity for nAChRs and may deserve further investigation as a possible PET radiotracer.     

Bromine-76 and carbon-11 labelled NNC 13-8199, metabolically stable benzodiazepine receptor agonists as radioligands for positron emission tomography

NNC 13-8241 has recently been labelled with iodine-123 and developed as a metabolically stable benzodiazepine receptor ligand for single-photon emission computed tomography (SPECT) in monkeys and man. NNC 13-8199 is a bromo-analogue of NNC 13-8241. This partial agonist binds selectively and with subnanomolar affinity to the benzodiazepine receptors. We prepared 76Br labelled NNC 13-8199 from the trimethyltin precursor by the chloramine-T method. Carbon-11 labelled NNC 13-8199 was synthesised by N-alkylation of the nitrogen of the amide group with [11C]methyl iodide. Positron emission tomography (PET) examination with the two radioligands in monkeys demonstrated a high uptake of radioactivity in the occipital, temporal and frontal cortex. In the study with [76Br]NNC 13-8199, the monkey brain uptake continued to increase until the time of displacement with flumazenil at 215 min after injection. For both radioligands the radioactivity in the cortical brain regions was markedly reduced after displacement with flumazenil. More than 98% of the radioactivity in monkey plasma represented unchanged radioligand 40 min after injection. The low degree of metabolism indicates that NNC 13-8199 is metabolically much more stable than hitherto developed PET radioligands for imaging of benzodiazepine receptors in the primate brain. [76Br]NNC 13-8199 has potential as a radioligand in human PET studies using models where a slow metabolism is an advantage.     

The interdisciplinary team''s approach to lupus nephritis

BACKGROUND: Animal and postmortem studies indicate that neuroleptic therapy may induce D2 dopamine receptor up-regulation in the basal ganglia. METHODS: To address this phenomenon in a clinical study, we investigated the D2 dopamine receptor binding in 15 DSM-III-R schizophrenics in the drug-naive state and 3 days after completion of a standardized neuroleptic therapy (benperidol 12-16 mg/day, for 25 days) using single photon emission computed tomography (SPECT). SPECT scans were obtained 2 hours after intravenous injection of 185 MBq 123I-iodobenzamide. For analysis, basal ganglia to frontal cortex (BG/FC) ratios were calculated and the patient sample was subgrouped into patients with a favorable versus a poor treatment response. RESULTS: Neuroleptic treatment led to decreased BG/FC ratios in patients with a favorable response, but increased ratios in the poor responders (df = 1, F = 4.1, p = .06). Changes of BG/FC ratios were significantly correlated with extrapyramidal side effects but not with neurological soft signs. CONCLUSIONS: Our findings suggest that neuroleptic therapy may induce D2 dopamine receptor up-regulation in a subgroup of patients characterized by poor treatment response and pronounced extrapyramidal side effects.     

Iodine-123-iodobenzamide binding in parkinsonism: reduction by dopamine agonists but not L-Dopa

The aim of the present study was to investigate the effect of treatment with L-Dopa or a dopamine agonist, or both, on specific striatal 123I-iodobenzamide (IBZM) binding using an intraindividual longitudinal design. METHOD: We prospectively studied the effect of dopaminomimetic treatment on specific [123I]IBZM binding measured by SPECT in 29 patients with a clinical diagnosis of Parkinson's disease, none of whom had previously received dopaminomimetic drugs. The patients had been selected on the basis of normal subsequent specific [123I]IBZM binding, semiquantitatively calculated as the basal ganglia/frontal cortex ratio, and a positive response to the dopamine agonist apomorphine before initiation of dopaminomimetic therapy. A second 123I-IBZM SPECT investigation was performed after 3-6 mo of treatment with L-Dopa or a dopamine agonist, or both. RESULTS: Specific [123I]IBZM binding was unchanged in 10 patients treated with L-Dopa alone. However, after treatment with a dopamine agonist there was a significant decline in specific [123I]IBZM binding (p < 0.05). After treatment with a combination of L-Dopa and a dopamine agonist, specific [123I]IBZM binding was reduced without reaching a level of significance (p = 0.08). CONCLUSION: Short-term treatment with a dopamine agonist but not with L-Dopa reduces specific [123I]IBZM binding. Therefore, before performing an [123I]IBZM SPECT scan in patients previously treated with dopaminomimetic drugs, dopamine agonists should be discontinued.     

Challenging the anterior attentional system with a continuous performance task: a functional magnetic resonance imaging approach

Combining the Continuous Performance Test (CPT) with a modern functional imaging technique provides a powerful tool for investigating neurophysiological processes in the human brain. There is increasing evidence from single photon emission tomography (SPECT), positron emission tomography (PET) and presently also functional magnetic resonance imaging (fMRI) studies proposing the existence of a distributed large-scale attentional network, mediated by the dorsolateral prefrontal and mesial frontal cortex, thalamus, basal ganglia and posterior parietal and superior temporal lobe. The aim of this study is to show that fMRI is a useful tool for in vivo localization of attentional tasks and to compare the results with established imaging techniques. Functional MRI was performed on a clinical 1.5-T system using gradient-echo acquisition. For data processing, the Statistical Parametric Mapping (SPM96) package was used. A right lateralized activation pattern in the dorsolateral prefrontal and mesial frontal cortex, the thalamus and the basal ganglia was found in a group of 12 male subjects. These findings support theories suggesting right hemispheric dominance of human attention.     

Metabolic anatomy of focal motor seizures

Contralateral focal seizures occurred in rats following the intracortical injection of penicillin into the anterior motor cortex. The anatomic dimensions of the metabolic response in the focus as well as the spread of increased activity through the brain were studied by autoradiography following intravenous injection of carbon 14-labeled 2-deoxyglucose. Injections of 25 to 200 units of penicillin resulted in mild to severe contralateral motor jerks coincident with repetitive single spike discharges on the electroencephalogram. Concurrent autoradiography revealed a 1.3- to 2.5-fold increase in metabolic activity in discrete areas in ipsilateral cortex, basal ganglia, thalamus, and contralateral cerebellum. Intracortical injections of over 300 units resulted in the development of recurrent contralateral tonic-clonic seizures, with 20% becoming bilateral. In brains of these animals there was activation of bilateral medial frontal cortex, bilateral extrapyramidal system, thalamus, cerebellum, and limbic structures.     

A quantitative study of regional cerebral blood flow in childhood using 123I-IMP-SPECT: with emphasis on age-related changes

Single photon emission computed tomography (SPECT), using N-isopropyl-p-[123I] iodoamphetamine (123I-IMP) was used for quantitative analysis of regional cerebral blood flow (rCBF) on 26 individuals between 0 and 19 years of age. The rCBF showed age-related changes; it was low in early infancy, increased in late infancy through early childhood, and decreased and remained constant after puberty. The rCBF through cerebral cortex varied more greatly than through thalamus and cerebellum, and seemed to depend more closely on age. In the case of 4 months of age rCBF was very low at the frontal region and was very high at the occipital region. In more older cases, rCBF in the cerebral cortex was higher than in the thalamus. In childhood, rCBF was very inconsistent and showed a great inter-individual variance.     

Brain regional neuropeptide changes resulting from social defeat.

Past work has demonstrated robust brain changes in cholecystokinin (CCK-8) following social defeat. Here the authors analyzed brain regional, CCK-8, substance P, corticotropin releasing factor (CRF), and neuropeptide Y levels in adult male Long-Evans rats defeated in a resident-intruder social aggression paradigm, as indexed by elevated bites received, freezing, and emission of 20-kHz calls. Brains harvested 6 hr after social defeat were dissected into 12 regions (olfactory bulbs, 3 cortical regions [frontal cortex, cortex above the basal ganglia, cortex above the diencephalon], caudate-putamen, basal forebrain, hypothalamus, hippocampus, thalamus, tectum, tegmentum, and lower brain stem). Neuropeptide radioimmunoassays demonstrated the following statistically significant regional changes in defeated rats as compared with nondefeated rats: CCK-8 was reduced in frontal cortex and cortex overlying diencephalon, the olfactory bulbs, caudate-putamen, hippocampus, tectum, and lower brainstem. Neuropeptide Y was elevated in the caudate-putamen. Substance P was elevated in the cortex over the basal ganglia and decreased in basal forebrain. CRF was diminished in the hippocampus. The results highlight more robust CCK modulation by social defeat as compared with 3 other neuropeptide systems involved in brain emotional regulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men

Interictal brain SPECT is useful for the localization of a seizure focus. Concomitant hypoperfusion of the ipsilateral thalamus on interictal SPECT has been noted for temporal lobe epilepsy. In this study, we aimed to evaluate the prevalence of thalamic hypoperfusion ipsilateral to temporal hypoperfusion (ipsilateral thalamic hypoperfusion) and to assess the usefulness of this finding for the lateralization of epileptic foci on interictal SPECT for temporal lobe epilepsy patients. METHODS: Forty-six patients with refractory temporal lobe epilepsy underwent interictal brain SPECT after intravenous injection of 555-740 MBq of 99mTc-ECD. Perfusion impairments in the brain, especially the temporal lobe and thalamus, were evaluated. The localization of seizure foci was determined in conjunction with scalp, ictal and cortical electroencephalography, MRI and clinical outcomes. Ictal SPECT was performed for 5 of the 12 patients. RESULTS: Concomitant decreased perfusion in both the temporal lobe and the ipsilateral thalamus was observed for 12 (26%) of 46 temporal lobe epilepsy patients on interictal brain SPECT. Seven patients showed hypoperfusion in the left temporal lobe and ipsilateral thalamus. Five patients showed hypoperfusion in the right temporal lobe and ipsilateral thalamus. In addition, hypoperfusion in the ipsilateral basal ganglia (ten patients) or contralateral cerebellum (four patients) was observed. CONCLUSION: Ipsilateral thalamic hypoperfusion is not uncommon in temporal lobe epilepsy. The exact mechanism causing ipsilateral thalamic hypoperfusion is uncertain; however, corticothalamic diaschisis may be an important factor. This finding may aid in the lateralization of seizure foci on interictal brain SPECT.     

Visceral afferent stimulation-evoked changes in the release of peptides into the parabrachial nucleus in vivo

OBJECTIVE: Although there is evidence from postmortem studies suggestive of deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) in schizophrenia, no direct in vivo evidence has been obtained to date. The authors used single photon emission computed tomography (SPECT) with iodine-123-labeled iomazenil ([123I]iomazenil), a radioligand that selectively binds with high affinity to the benzodiazepine subunit of the GABAA receptor complex in the human brain, to investigate the presence of benzodiazepine receptor abnormalities in the cerebral cortex of living subjects with schizophrenia. METHOD: Dynamic [123I]iomazenil SPECT was performed in 15 patients (14 patients with DSM-III-R schizophrenia and one with schizophreniform disorder) and 12 healthy subjects over a period of 2 hours. The time-integral method was used to generate ratios of "specific" to "nonspecific" [123I]iomazenil binding at equilibrium for several cortical regions. RESULTS: No overall between-group differences in benzodiazepine receptor binding were found, but significant correlations emerged between the severity of schizophrenic symptoms and [123I]iomazenil binding in limbic cortical regions: positive symptom scores were negatively correlated with benzodiazepine receptor binding in the left medial temporal region, and negative symptoms were inversely related to receptor binding in the medial frontal region. These correlations were not significant when a Bonferroni correction for multiple comparisons was applied. CONCLUSIONS: These preliminary results are consistent with previous research implicating limbic cortical regions in the pathophysiology of schizophrenia, suggesting that reduced inhibitory GABAergic tone in these areas may contribute to the appearance of schizophrenic symptoms.     

Technetium-99m-HMPAO brain SPECT in systemic lupus erythematosus with CNS involvement

Functional brain SPECT is playing an increasingly important role in evaluating CNS conditions in patients with systemic lupus erythematosus (SLE). However, SPECT findings varied in different studies because of their small population. Furthermore, earlier researchers, being restricted by the resolution of the camera, might not have been able to evaluate deep-seated nuclei such as the basal ganglia and thalamus. In this study, we describe the different patterns of SPECT findings in SLE patients with CNS involvement. METHODS: Seventy-two SLE patients (aged 14-67 yr; mean 33.2 yr) were divided into three groups: Group 1 with definite neuro-psychiatric disorder (including stroke, seizures and psychosis); Group 2 with minor neuropsychiatric disorders (headache, dizziness and recent memory impairment); and Group 3 without any neuropsychiatric symptoms or signs. Ninety minutes after injection of 1110 MBq 99mTc-HMPAO, brain SPECT was performed using a dual-head camera and fan-beam collimator. In addition, MRI and an electroencephalography (EEG) were also performed. RESULTS: SPECT findings were normal in 87% of the Group 3 patients and abnormal in all Group 1 patients; 84.6% of the Group 2 patients had abnormal SPECT findings. The parietal, frontal and temporal lobes were the most common areas of CNS involvement. Parietal lobes were involved in 95.6% of Group 1 patients and 80.7% in Group 2 patients. Frontal lobes were involved in 56.5% of Group 1 patients and 65.3% of Group 2 patients. Temporal lobes were involved in 56.5% of Group 1 patients and 46.1% of Group 2 patients. The basal ganglion was involved in about 30% of Group 1 patients and 11.5% of Group 2 patients, while the thalamus and cerebellum were less involved in neuropsychiatric SLE. MR images showed less sensitivity in the detection of CNS involvement than the SPECT and were normal in 27.3% of patients with definite neuropsychiatric disorders. The EEG and anticardiolipin antibody did not correlate well to the clinical diagnosis. CONCLUSION: HMPAO brain SPECT had the best correlation with the clinical diagnosis and may provide additional and objective information on SLE patients with potential CNS involvement.     

Identification of four classes of brain nicotinic receptors using beta2 mutant mice

Although the expression patterns of the neuronal nicotinic acetylcholine receptor (nAChR) subunits thus far described are known, the subunit composition of functional receptors in different brain areas is an ongoing question. Mice lacking the beta2 subunit of the nAChR were used for receptor autoradiography studies and patch-clamp recording in thin brain slices. Four distinct types of nAChRs were identified, expanding on an existing classification [Alkondon M, Albuquerque EX (1993) Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes. J Pharmacol Exp Ther 265:1455-1473.], and tentatively identifying the subunit composition of nAChRs in different brain regions. Type 1 nAChRs bind alpha-bungarotoxin, are not altered in beta2 -/- mice, and contain the alpha7 subunit. Type 2 nAChRs contain the beta2 subunit because they are absent in beta2 -/- mice, bind all nicotinic agonists used with high affinity (excluding alpha-bungarotoxin), have an order of potency for nicotine > cytisine in electrophysiological experiments, and are likely to be composed of alpha4 beta2 in most brain regions, with other alpha subunits contributing in specific areas. Type 3 nAChRs bind epibatidine with high affinity in equilibrium binding experiments and show that cytisine is as effective as nicotine in electrophysiological experiments; their distribution and persistence in beta2 -/- mice strongly suggest a subunit composition of alpha3 beta4. Type 4 nAChRs bind cytisine and epibatidine with high affinity in equilibrium binding experiments and persist in beta2 -/- mice; cytisine = nicotine in electrophysiological experiments. Type 4 nAChRs also exhibit faster desensitization than type 3 nAChRs at high doses of nicotine. Knock-out animals lacking individual alpha subunits should allow a further dissection of nAChR subclasses.     

A test-retest study of cerebral blood flow during somatosensory stimulation in depressed patients with schizophrenia and major depression

Six depressed patients with schizophrenia and 6 depressed patients with major depression were investigated before and during somatosensory stimulation (SS) with Tc-99m HMPAO SPECT. 8 controls were investigated only under resting conditions. The results can be summarized as follows: 1. Both psychiatric patient groups were hypofrontal (dorsolateral prefrontal cortex) compared to controls. 2. Hypofrontality was further enhanced by SS, significantly only in affective psychoses in the right inferior frontal lobe and in the right frontal hemisphere in total, in schizophrenia in the left dorsolateral prefrontal cortex. 3. Within the frontal lobes different regions were affected by SS in the two diagnostic groups. 4. In the right inferior parietal lobe SS response was significantly different in the two illnesses with schizophrenia showing a relative decrease, affective psychoses showing a relative increase of activity. 5. SS produced an increase of cerebral blood flow in subcortical regions (statistically significant contralateral to SS in thalamus and basal ganglia, ipsilateral to SS in cerebellum), a pattern which was common to all psychiatric patients. 6. Somatosensory cortex flow was not changed by SS. In conclusion, we could not fully confirm our hypotheses that similar blood flow abnormalities in different illnesses during SS are only caused by similarities in depressive psychopathology. Instead, depressed patients with schizophrenia were different from depressed patients with major depression in showing decreased activity in interrelating brain regions participating in an attentional network.     

In vivo labelling of the mouse brain 5-hydroxytryptamine1A receptor with the novel selective antagonist 3H-NAD-299

The in vivo labelling of 5-hydroxytryptamine (5-HT)1A receptors in the mouse brain was studied with the novel selective 5-HT1A receptor antagonist, NAD-299 ((R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran- 5-carboxamide hydrogen (2R,3R)-tartrate monohydrate). 3H-NAD-299 was injected in a tail vein and the radioactivity in various brain regions was determined. More than 90% of the radioactivity in hippocampus, 15 min after the injection, was intact NAD-299. At this time the amount of 3H-NAD-299 was highest in hippocampus followed by frontal cortex, mesencephalon, hypothalamus, striatum and cerebellum. The specific accumulation of radioactivity (after subtracting cerebellum values) in frontal cortex and hippocampus was maximal 10 to 30 min after the injection and had almost disappeared after 2 h. Saturation kinetics derived Bmax (pmol/g wet weight tissue) values of 19.6+/-2.0 in frontal cortex and 38.0+/-3.5 in hippocampus. The apparent Kd values expressed in nmol/kg 3H-NAD-299 injected, were 12.3+/-2.2 in frontal cortex and 20.3+/-3.1 in hippocampus. The 5-HT1A receptor antagonist, WAY-100,635 competitively inhibited the specific accumulation of 3H-NAD-299 and was about equipotent with unlabelled NAD-299 with ED50 values of 20-30 nmol/kg s.c. These compounds were about 10 times more potent than the 5-HT1A receptor antagonists, p-MPPI and NDL-249 and 100 times more potent than (S)-UH-301. 5-HT1A receptor agonists, e.g. 8-OH-DPAT and flesinoxan and partial agonists, e.g. pindolol, buspirone and ipsapirone had low potency in this in vivo assay. Spiperone and methiothepin inhibited the 3H-NAD-299 accumulation at 10 micromol/kg s.c. The alpha1-adrenoceptor antagonist, prazosin at 2 micromol/kg s.c. increased significantly the specific accumulation of 3H-NAD-299. Pretreatment of the mice with the non-selective, irreversible receptor antagonist, EEDQ produced a dose related long-lasting decrease in the accumulation of 3H-NAD-299. It is concluded that NAD-299 is a very suitable ligand for studies of 5-HT1A receptors in the brain in vivo.     

Muscarinic cholinergic receptor measurements with [18F]FP-TZTP: control and competition studies

[18F]Fluoropropyl-TZTP (FP-TZTP) is a subtype-selective muscarinic cholinergic ligand with potential suitability for studying Alzheimer's disease. Positron emission tomography studies in isofluorane-anesthetized rhesus monkeys were performed to assess the in vivo behavior of this radiotracer. First, control studies (n = 11) were performed to characterize the tracer kinetics and to choose an appropriate model using a metabolite-corrected arterial input function. Second, preblocking studies (n = 4) with unlabeled FP-TZTP were used to measure nonspecific binding. Third, the sensitivity of [18F]FP-TZTP binding to changes in brain acetylcholine (ACh) was assessed by administering physostigmine, an acetylcholinesterase (AChE) inhibitor, by intravenous infusion (100 to 200 microg x kg(-1) x h(-1)) beginning 30 minutes before tracer injection (n = 7). Tracer uptake in the brain was rapid with K1 values of 0.4 to 0.6 mL x min(-1) x mL(-1) in gray matter. A model with one tissue compartment was chosen because reliable parameter estimates could not be obtained with a more complex model. Volume of distribution (V) values, determined from functional images created by pixel-by-pixel fitting, were very similar in cortical regions, basal ganglia, and thalamus, but significantly lower (P < 0.01) in the cerebellum, consistent with the distribution of M2 cholinergic receptors. Preblocking studies with unlabeled FP-TZTP reduced V by 60% to 70% in cortical and subcortical regions. Physostigmine produced a 35% reduction in cortical specific binding (P < 0.05), consistent with increased ACh competition. The reduction in basal ganglia (12%) was significantly smaller (P < 0.05), consistent with its markedly higher AChE activity. These studies indicate that [18F]FP-TZTP should be useful for the in vivo measurement of muscarinic receptors with positron emission tomography.