Peripheral benzodiazepine receptor (PBR) is expressed in most organs and its expression is reported to be increased in activated microglia in the brain. [(11)C]PK11195 has been widely used for the in vivo imaging of PBRs, but its signal in the brain was not high enough for stable quantitative analysis. We synthesized a novel positron emission tomography (PET) ligand, [(11)C]DAA1106, for PBR and investigated its in vivo properties in rat and monkey brain. High uptake of [(11)C]DAA1106 was observed in the olfactory bulb and choroid plexus area, followed by the pons/medulla and cerebellum by in vivo autoradiography of rat brain, correlating with the binding in vitro. [(11)C]DAA1106 binding was increased in the dorsal hippocampus with neural destruction, suggesting glial reaction. [(11)C]DAA1106 binding was both inhibited and displaced by 1.0 mg/kg of DAA1106 and 5 mg/kg of PK11195 by 80% and 70%, respectively. Specific binding was estimated as 80% of total binding. [(11)C]DAA1106 binding was four times higher compared to the binding of [(11)C]PK11195 in the monkey occipital cortex. These results indicated that [(11)C]DAA1106 might be a good ligand for in vivo imaging of PBR.

When playing a video game, or using a teleoperator system, we feel our self-image projected into the video monitor as a part of or an extension of ourselves. Here we show that such a self image is coded by bimodal (somatosensory and visual) neurons in the monkey intraparietal cortex, which have visual receptive fields (RFs) encompassing their somatosensory RFs. We earlier showed these neurons to code the schema of the hand which can be altered in accordance with psychological modification of the body image; that is, when the monkey used a rake as a tool to extend its reach, the visual RFs of these neurons elongated along the axis of the tool, as if the monkey's self image extended to the end of the tool. In the present experiment, we trained monkeys to recognize their image in a video monitor (despite the earlier general belief that monkeys are not capable of doing so), and demonstrated that the visual RF of these bimodal neurons was now projected onto the video screen so as to code the image of the hand as an extension of the self. Further, the coding of the imaged hand could intentionally be altered to match the image artificially modified in the monitor.

No abstract

To develop a positron emission tomography (PET) ligand for imaging the 'peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four analogues (4-7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR. Of these compounds, fluoromethyl (4) and fluoroethyl (5) analogues had similar or higher affinities for PBR than the parent compound 2 (K(i) = 0.16 nM for PBR in rat brain sections). Iodomethyl analogue 6 displayed a moderate affinity, whereas tosyloxyethyl analogue 7 had weak affinity. Radiolabeling was performed for the fluoroalkyl analogues 4 and 5 using fluorine-18 ((18)F, beta(+); 96.7%, T(1/2) = 109.8 min). Ligands [(18)F]4 and [(18)F]5 were respectively synthesized by the alkylation of desmethyl precursor 3 with [(18)F]fluoromethyl iodide ([(18)F]8) and 2-[(18)F]fluoroethyl bromide ([(18)F]9). The distribution patterns of [(18)F]4 and [(18)F]5 in mice were consistent with the known distribution of PBR. However, compared with [(18)F]5, [(18)F]4 displayed a high uptake in the bone of mice. The PET image of [(18)F]4 for monkey brain also showed significant radioactivity in the bone, suggesting that this ligand was unstable for in vivo defluorination and was not a useful PET ligand. Ligand [(18)F]5 displayed a high uptake in monkey brain especially in the occipital cortex, a region with richer PBR than the other regions in the brain. The radioactivity level of [(18)F]5 in monkey brain was 1.5 times higher than that of [(11)C]2, and 6 times higher than that of (R)-(1-(2-chlorophenyl)-N-[(11)C]methyl,N-(1-methylpropyl)isoquinoline ([(11)C]1). Moreover, the in vivo binding of [(18)F]5 was significantly inhibited by PBR-selective 2 or 1, indicating that the binding of [(18)F]5 in the monkey brain was mainly due to PBR. Metabolite analysis revealed that [(18)F]4 was rapidly metabolized by defluorination to [(18)F]F(-) in the plasma and brain of mice, whereas [(18)F]5 was metabolized by debenzylation to a polar product [(18)F]13 only in the plasma. No radioactive metabolite of [(18)F]5 was detected in the mouse brain. The biological data indicate that [(18)F]5 is a useful PET ligand for PBR and is currently used for imaging PBR in human brain.

No abstract

No abstract

No abstract

1 We examined regeneration of endothelial cells (ECs), neointima formation, decreased endotheliumdependent relaxation (EDR) and changes in the contents of L-arginine, NG-monomethyl-L-arginine (L-NMMA), asymmetrical NG, N0-dimethylarginine (ADMA) and symmetrical NG,NG-dimethylarginine (SDMA) in the regnerated ECs, 6 weeks after balloon denudation of the rabbit carotid artery. 2 Regeneration of ECs was completed in 6 weeks and a significant neointima formation accompanied by the decreased EDR was observed. 3 L-NMMA and ADMA contents in the regenerated ECs (23.5 + 4.3 and 21.2 + 2.0 pmol mg-' DNA, respectively) were significantly (P <0.05 and P <0.01) higher than those in the control ECs (8.8 + 3.0 and 7.4 + 1.9 pmol mg'l DNA, respectively), whereas L-arginine was significantly (P < 0.005) decreased in the regenerated ECs (31,470+1,050 pmol mg-' DNA) as compared to that in the control ECs (47,870+ 1,890 pmol mg-' DNA). SDMA content was below the assay limits. 4 L-NMMA and ADMA, but not SDMA, inhibited the EDR induced by acetylcholine in a concentration-dependent manner. The inhibition with L-NMMA and ADMA was prevented by an addition of L-arginine, but not by D-arginine. 5 These results suggest that the accumulation of endogenous inhibitors for nitric oxide synthesis and decreased L-arginine content are associated with decreased NO production/release from regenerated ECs and neointima formation. Keywords: Neointima formation; endogenous inhibitors for NO synthesis; balloon denudation; decreased endotheliumdependent relaxation; EDRF/NO Introduction MethodsAs proposed by Ross & Glomset (1976a,b) and Ross (1986), denudation and nondenudation intimal injuries may play an important role in the development of atherosclerotic vascular disease (Ip et al., 1990). We have reported that restoration of the endothelium after balloon denudation of the rabbit carotid artery was completed in 6 weeks and that regenerated ECs were less capable of producing/releasing the endothelium-derived relaxing factor (EDRF/nitric oxide: NO) (Azuma et al., 1990;Niimi et al., 1994). EDRF/NO inhibits platelet adhesion and aggregation (Azuma et al., 1986;Radomski et al., 1987), which is considered as an initiating event for neointima formation (Ross, 1986;Schwartz et al., 1981). It has also been demonstrated that NO inhibits smooth muscle cell proliferation (Garg & Hassid, 1989). These findings when considered together suggest that the neointima formation after endothelial removal might be caused at least partly through impairment of the ability of ECs to produce/release EDRF/NO. However, the mechanism by which the production/release of EDRF/NO is reduced remains unclear. Recently, Vallance et al. (1992) have obtained evidence NG-monomethyl-L-arginine (L-NMMA) and asymmetrical NG,NG-dimethyl arginine (ADMA) play a role as endogenous inhibitors of NO synthesis. The present experiments were, therefore, designed to determine the regeneration of ECs, the neointima formation, the decreased EDR and the changes in content of L-arginine, L-NMMA, ADMA an...