Functional brain mapping of monkey tool use.

When using a tool, we can perceive a psychological association between the tool and the body parts-the tool is incorporated into our "body-image." During tool use, visual response properties of bimodal (tactile and visual) neurons in the intraparietal area of the monkey's cerebral cortex were modified to include the hand-held tool. Visual properties of the monkey intraparietal neurons may represent the body-image in the brain. We explored tool use-induced activation within the intraparietal area and elsewhere in alert monkey brain using positron emission tomography (PET). Tool use-related activities compared with the control condition (simple-stick manipulation) revealed a significant increase in cerebral blood flow in the corresponding intraparietal region, basal ganglia, presupplementary motor area, premotor cortex, and cerebellum. These tool use-specific areas may participate in maintaining and updating the body-image for the precise guidance of a hand-held rake onto a distant reward.

Regioselective nucleophilic additions to cross-conjugated dienone system bearing beta-fluorine: a versatile approach to highly substituted 2-cyclopentenones.

[reaction: see text] 3-Fluoro-5-methylene-2-cyclopentenone is treated with appropriate nucleophiles and Lewis acids to undergo regioselective 1,2-addition, exocyclic 1,4-addition, and endocyclic 1,4-addition, leading to 3-substituted 4-methylene-2-cyclopentenones, 5-substituted 3-fluoro-2-cyclopentenones, and 3-substituted 5-methylene-2-cyclopentenones in good yields, respectively.

Effect of endogenous dopamine on extrastriatal [¹¹C]FLB 457 binding measured by PET.

Central dopaminergic systems are known to be implicated in the pathophysiology of schizophrenia and recent in vivo dopamine receptor imaging studies have focused on the measurement of extrastriatal dopamine receptor. However, there are only a limited number of ligands that can measure the low-density D2 receptor in extrastriatal regions and their sensitivity to endogenous dopamine in extrastriatal regions has not yet been fully examined. In this study, the effect of endogenous dopamine on the extrastriatal binding of [11C]FLB 457 was examined in the rhesus monkey after facilitation with 1 mg/kg of methamphetamine (MAP) and was compared with the effect on the striatal binding of [11C]raclopride. The indices of receptor binding were obtained by four methods using cerebellum as a reference region. The bindings of [11C]FLB 457 in the frontal cortex, temporal cortex, and thalamus were not significantly changed after MAP treatment, while the striatal binding of [11C]raclopride was decreased by more than 20%. These results suggest that [11C]FLB 457 is not sensitive to endogenous dopamine in the extrastriatal regions of rhesus monkeys, despite a sufficient dose of MAP to decrease the binding of [11C]raclopride in the striatum.

Lewis acid-promoted deoxygenative di[beta,beta-bis(ethylthio)]vinylation of aldehydes with trimethylsilylketene bis(ethylthio)acetal.

Silylketene dithioacetal 1 reacted with aldehydes 2a-o, 14, or cinnamaldehyde (11) in the presence of Lewis acid to give deoxygenative divinylation products, 3-substituted 1,4-pentadienes 3a-o, 15, or 5-phenyl-1,3,6-heptatriene 13b, in good to moderate yields. Similar reaction with 2-aminobenzaldehyde (16) or salicylaldehyde (17) produced quinoline 19 or chroman 20 in 40-58% yield. Treatment of 1 with alpha-diketones 22a-c or alpha-ketoester 24 led to tetrasubstituted furans 23a-c or allylic alcohol 25, respectively, in rather low yields. The formation mechanisms of these products are discussed.

In vivo binding properties of [carbonyl-11C]WAY-100635: effect of endogenous serotonin.

[Carbonyl-(11)C]WAY-100635 has been reported to be a useful ligand for the investigation of 5-HT(1A) receptor imaging in vivo. However, the cellular distribution and the influence of endogenous serotonin (5-HT) on in vivo binding have not been fully examined. In this study, we investigated the effect of 5,7-dihydroxytryptamine-produced destruction of 5-HT neurons, reserpine-induced 5-HT depletion, and fenfluramine-induced 5-HT increase on [carbonyl-(11)C]WAY-100635 binding in vivo. There was no significant change in the uptake of [carbonyl-(11)C]WAY-100635 in the slice of 5-HT denervated rat brain except in the raphe nucleus, where 5-HT cell bodies exist. There was no obvious effect of enhanced 5-HT release by fenfluramine or decreased release by reserpine on [carbonyl-(11)C]WAY-100635 binding in the dissected brain region. No significant effect was observed in the time course of [carbonyl-(11)C]WAY-100635 in the hippocampus and frontal cortex measured by PET. These results indicated that the in vivo binding of [carbonyl-(11)C]WAY-100635 in the hippocampus and cerebral cortex mainly reflects postsynaptic 5-HT(1A) receptor binding, and that this binding is not sensitive to endogenous 5-HT.

4,5,9,10-Tetrahydro-1,4-ethanobenz[b]quinolizine as a prodrug for its quinolizinium cation as a ligand to the open state of the TCP-binding site of NMDA receptors.

A new derivative of 4,5,9,10-tetrahydro-1,4-ethanobenz[b]quinolizine (2) has been designed as a prodrug for its quinolizinium cation (1) that is a potent antagonist of the TCP-binding site of NMDA receptors at the open state. The 11C-labeled 2 showed high accumulation of radioactivity in the brain in an in vivo biodistribution study. The speculation of 2 as a prodrug of 1 has been proven by the fact that 1 was observed in a high ratio to 2 in an analysis by RP-HPLC of the brain homogenates.

A prodrug of NMDA/glycine site antagonist, L-703,717, with improved BBB permeability: 4-acetoxy derivative and its positron-emitter labeled analog.

4-Acetoxy derivative (1) of L-703,717, a high-affinity (IC50=4.5 nM) antagonist for the glycine site of NMDA receptors, was synthesized and its brain uptake was examined using a carbon-11 labeled analog ([11C]1). Initial radioactivity in the brain after intravenous injection of [11C]1 was a 2-fold that of [11C]L-703,717 in mice. Rapid bioconversion of [11C]1 into [11C]L-703,717 was demonstrated by metabolite analyses of rat brain after [11C]1 injection. Ex vivo autoradiography of [11C]1 in rat brain showed the same cerebellar localization of radioactivity as [11C]L-703,717. These results indicate that 1 is a promising pharmacological tool as a prodrug of L-703,717 with improved BBB permeability.

A strategy for increasing the brain uptake of a radioligand in animals: use of a drug that inhibits plasma protein binding.

A positron-emitter labeled radioligand for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor, [(11)C]L-703,717, was examined for its ability to penetrate the brain in animals by simultaneous use with drugs having high-affinity separate binding sites on human serum albumin. [(11)C]L-703,717 has poor blood-brain barrier (BBB) permeability because it binds tightly to plasma proteins. Co-injection of warfarin (50-200 mg/kg), a drug that binds to albumin and resembles L-703,717 in structure, dose-dependently enhanced the penetration by [(11)C]L-703,717 in mice, resulting in a five-fold increase in the brain radioactivity at 1 min after the injection. Drugs structurally unrelated to L-703,717, salicylate, phenol red, and L-tryptophan, were less effective or ineffective in increasing the uptake of [(11)C]L-703,717. These results suggest that the simultaneous use of a drug that inhibits the binding of a radioligand to plasma proteins is a useful way to overcome the poor BBB permeability of the radioligand triggered by its tight binding to plasma proteins. In brain distribution studies in rodents, it was found that, after the increase in brain uptake with warfarin, much of the glycine site antagonist accumulates in the cerebellum but its pharmacological specificity did not match the glycine site of NMDA receptors.

Synthesis and Synthetic Application of alpha-Formylvinylphosphonates. Facile Synthesis of Phosphono-Substituted Heterocyclic Compounds.

The beta-ethoxy-alpha-phosphonovinyl anion, generated from beta-(ethoxy)vinylphosphonate 1 and LDA, reacted with aldehydes and ketones or phenyl isocyanate to give the corresponding allylic alcohols 2a-m or 1,3-diphenyl-5-phosphonouracil 4 in good or moderate yields. Treatment of the alcohols 2a-d,g,h,j with trifluoroacetic acid led to alpha-formylvinylphosphonates 5a-d,g,h,j in excellent yields. Synthetic application of the alpha-formylvinylphosphonates 5a-d,g,h to phosphono-substituted heterocyclic compounds was studied.

A focused compound library of novel N-(7-indolyl)benzenesulfonamides for the discovery of potent cell cycle inhibitors.

A series of compounds containing an N-(7-indolyl)benzenesulfonamide pharmacophore was synthesized and evaluated as a potential antitumor agent. Cell cycle analysis with P388 murine leukemia cells revealed that there were two different classes of potent cell cycle inhibitors; one disrupted mitosis and the other caused G1 accumulation. Herein described is the SAR summary of the substituent patterns on this pharmacophore template.

A general method for acylation of indoles at the 3-position with acyl chlorides in the presence of dialkylaluminum chloride.

[reaction--see text] Indoles are selectively acylated at the 3-position in high yields on treatment with a wide variety of acyl chlorides in CH(2)Cl(2) in the presence of diethylaluminum chloride or dimethylaluminum chloride. The reaction proceeds under mild conditions and is applicable to indoles bearing various functional groups without NH protection.

Discovery of novel antitumor sulfonamides targeting G1 phase of the cell cycle.

Described herein is the discovery of a novel series of antitumor sulfonamides targeting G1 phase of the cell cycle. Cell cycle control in G1 phase has attracted considerable attention in recent cancer research, because many of the important proteins involved in G1 progression or G1/S transition have been found to play a crucial role in proliferation, differentiation, transformation, and programmed cell death (apoptosis). We previously reported our first antitumor sulfonamide E7010 as a novel tubulin polymerization inhibitor. Interestingly enough, continuous research on structurally related compounds led us to the finding of another class of antitumor sulfonamides that block cell cycle progression of P388 murine leukemia cells in G1 phase, but not in M phase. Of the compounds examined, N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) showed significant antitumor activity against HCT116 human colon carcinoma both in vitro (IC(50) 0.11 microg/mL in cell proliferation assay) and in vivo (not only growth suppression but also a marked reduction of tumor size in nude mice). Because of its promising efficacy against human tumor xenografts and its unique mode of action, E7070 is currently undergoing phase I clinical trials in European countries.

Muscarinic receptor occupancy by biperiden in living human brain.

Anticholinergic drug is often used to treat extrapyramidal symptoms. We measured muscarinic cholinergic receptor (mAchR) occupancy by the oral administration of biperiden in eight healthy subjects using positron emission tomography (PET) and [11C]N-methyl-4-piperidylbenzilate (NMPB). After the baseline scan each subject underwent one or two post-dose PET scans. mAchR occupancy was 10-45% in the frontal cortex three hours after the oral administration of 4 mg of biperiden. The occupancy correlated with the plasma concentration of biperiden in a curvilinear manner.

Muscarinic cholinergic receptors in human narcolepsy: a PET study.

OBJECTIVES: To investigate the function of the muscarinic cholinergic receptor (mAchR) in narcolepsy and the effects of pharmacotherapy on mAchRs. BACKGROUND: Muscarinic neural transmission serves as the main executive system in REM sleep. Studies in canine narcolepsy reported an increase in mAchRs in the pons. METHODS: The mAchRs of 11 drug naive/free patients with narcolepsy and 21 normal controls were investigated using PET with [11C]N-methyl-4-piperidylbenzilate ([11C]NMPB). Measurements were done in the pons, thalamus, striatum, and cerebral cortex. Seven of the 11 patients also underwent additional PET scans after the alleviation of symptoms by pharmacotherapy. RESULTS: There were no differences in [11C]NMPB binding between the control and drug naive/free patients in all areas analyzed. At the time of on-medication PET scan, [11C]NMPB binding in the thalamus was decreased, but only to a small degree compared with that by anticholinergic drugs. CONCLUSION: The present results do not support the notion that the mAchR is the main site of action of pharmacotherapy in the marked clinical improvement of human cataplexy.

Novel 6-5 fused ring heterocycle antifolates with potent antitumor activity: bridge modifications and heterocyclic benzoyl isosters of 2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine antifolate.

Structural modifications of an extremely potent inhibitor of dihydrofolate reductase (DHFR) activity and tumor cell growth, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic acid (1), have led to the synthesis of new cyclopenta[d]pyrimidine-based antifolates, including those with low alkyl substituted trimethylene bridges (2a, b) and isosterically modified bridges (ethyleneoxa, 2c; ethyleneamino, 2d; the N-methyl- and N-ethyl derivatives of 2d, 2e, f) and those in which the benzene ring of 1 has been replaced by heterocyclic isosters (indole, 2g; indoline, 2h; thiophene, 2i). These new analogs are highly potent as DHFR and cell growth inhibitors, and most of them are more potent than methotrexate (MTX) and 10-ethyl-10-deazapterin (10-EDAM) in inhibiting tumor cell growth (P388 MTX-sensitive and MTX-resistant, colon 26 and KB) on 72 h drug exposure. Among them, 2a (the 10-methyl derivative of 1) and 2i were most potent, being 2- to 3-fold more potent than 10-EDAM. On 4 h drug exposure, the growth-inhibitory activity of these analogs was radically influenced by even minor structural changes. Compounds 1, 2a--e, g--i were much more cytotoxic in colon 26 cell line than were MTX and 10-EDAM, with 2d and 2i being most potent, followed by 2a. Structure-activity relationships and their possible significance are discussed.

Measurement of somatostatin release in rat brain by microdialysis.

We determined the most suitable conditions for measuring the somatostatin (SRIF) level by brain microdialysis and investigated its release from the hypothalamus. The relative recovery rate of SRIF was 8.4 +/- 0.5% (mean +/- SE) using a polycarbonate (PC) membrane with the push-pull method at a flow rate of 2 microliters/min. Using tubes with an internal diameter of 0.28 mm and lengths of 5, 25, 50 and 100 cm, the relative recovery rates using a PC membrane with the push method were 8.2 +/- 0.5%, 7.3 +/- 0.6%, 6.2 +/- 0.5% and 4.1 +/- 0.6%, respectively. When using tubes with an internal diameter of 0.1 mm and lengths of 5, 25, 50 and 100 cm, the relative recovery rates were 7.3 +/- 0.7%, 5.6 +/- 1.0%, 3.5 +/- 1.1% and 1.4 +/- 0.7%, respectively. The relative recovery rate was 5.2 +/- 0.5% with a polysulfone (PS-F, Fresenius) membrane, 4.5 +/- 0.4% with a PS-H (Hospal) membrane, 2.6 +/- 0.2% with an ethylenevinyl alcohol membrane (EVAL), 5.1 +/- 0.8% with a polyvinyl alcohol (PVA) membrane and 10.4 +/- 0.8% with a PS-K (Kaneka) membrane. With the push method, the extracellular SRIF level in rat pituitary was 42.8 +/- 1.8 pg/ml with a PC membrane, 23.1 +/- 2.9 pg/ml with an EVAL membrane at a flow rate of 2 microliters/min. With the push-pull method, it was 52.7 +/- 5.2 pg/ml using a PC membrane, 33.5 +/- 2.8 pg/ml using a PVA membrane and 54.4 +/- 3.2 pg/ml using a PS-K membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Biosynthesis of agr and beta-Ecdysones from Cholesterol outside the Prothoracic Gland in Bombyx mori.

Labeling experiments have established that cholesterol is converted into alpha-and beta-ecdysones in isolated abdomens of silkworm larvae. Since the isolated abdomens do not contain the prothoracic glands, a doubt is cast on the long-standing principle in insect endocrinology that the prothoracic glands are the source of ecdysone secretion.