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1.
Véronique Strijckmans Michel Bottlaender Humin Luo Michèle Ottavianil Daniel W. McPherson Christian Loc'h Chantal Fuseau Furn F. Knapp Bernard Mazière 《European journal of nuclear medicine and molecular imaging》1997,24(5):475-482
We studied the potential of three radiobrominated isomers of BrQNP, (Z(-,-)-[76Br]BrQNP,E(-,-)-[76Br]BrQNP andE(-,+)-[76Br]BrQNP), as suitable radioligands for imaging of central muscarinic cholinergic receptors in the human brain. These radioligands were stereospecifically prepared by electrophilic radiobromodestannylation of the respective tributylstannyl precursors using no-carrier-added [76Br]BrNH4 and peracetic acid. Preliminary pharmacological characterizations were determined by biodistribution, autoradiography, competition, displacement and metabolite studies in rats. The (-,-)-configuration presented important specific uptakes in brain muscarinic cholinergic receptor (mAChR)-rich structures and in heart, low metabolization rates and an apparent M2 selectivity. The (-,+)-configuration revealed more rapid clearance, lower uptake, a higher metabolization rate and an apparent M1 selectivity. Reversibility of the binding was confirmed for the three radiotracers. Positron emission tomography in the living baboon brain revealed high and rapid uptake in the brain and accumulation in the mAChR-rich structures studied. At 30 min p.i., theE(-,-)-radiotracer reached a plateau in cortex, pons and thalamus with concentrations of 29%, 24% and 19% ID/l, respectively.Z(-,-)-[76Br]BrQNP also accumulated in these structures, reaching a maximal uptake (27% ID/l) in the cortex 2 h p.i. At 5 min p.i. a plateau (17% ID/l) was only observed in the cortex for theE(-,+)-[76Br]BrQNP; by contrast, the other structures showed slow washout. After 3 weeks, the (-,-)-radiotracers were studied in the same baboon pretreated with dexetimide (1 mg/kg), a well-known muscarinic antagonist. In all the mAChR structures, the highly reduced uptake observed after this preloading step indicates that these radiotracers specifically bind to muscarinic receptors.Z(-,-)-[76Br]BrQNP, which is displaced in higher amounts from M2 mAChR-enriched structures, reveals an M2 affinity. The two isomers having the (-,-)-configuration are potential probes for investigating central muscarinic receptors. The absolute configuration on the acetate chiral centre influences their muscarinic subtype selectivity and thecis-trans isomerism of the vinyl moiety affects their specific fixation. 相似文献
2.
Recent evidence suggests that the putative dopamine (DA) autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232, share some neurochemical and behavioral effects with both psychostimulants and neuroleptics. The ability of (+)-AJ 76 and (+)-UH 232 to mimic or antagonize the stimulus effects of cocaine was investigated in rats trained to discriminate 5 mg/kg (N=8) or 10 mg/kg (N=8) of cocaine from saline in a two-lever, water-reinforced, drug discrimination task. In the cocaine (10 mg/kg) group, administration of (+)-AJ 76 (2.5–20 mg/kg) engendered only a partial substitution for cocaine (maximum 60% cocaine-lever responses). Given in combination with cocaine (10 mg/kg), (+)-AJ 76 (2.5–40 mg/kg) did not significantly attenuate the cocaine cue. A fixed dose of (+)-AJ 76 (2.5 or 10 mg/kg) plus various doses of cocaine (1.25–5 mg/kg) did not alter the cocaine dose-response curve. (+)-UH 232 (2–16 mg/kg) produced primarily saline-appropriate responding in rats trained to discriminate 5 mg/kg of cocaine and was unable to block the interoceptive cocaine state when given in combination with cocaine (5 mg/kg). (+)-UH 232 (2 or 8 mg/kg) also did not alter the cocaine dose-response curve. These results suggest that (+)-AJ 76 and (+)-UH 232 elicit only weak or no cocaine-like stimulus effects and, unlike neuroleptics, do not attenuate the cocaine cue. 相似文献
3.
Christian Foged Christer Halldin Christian Loc’h Bernard Mazière Stefan Pauli Mariannick Maziére Holger C. Hansen Tetsuya Suhara Carl-Gunnar Swahn Per Karlsson Lars Farde 《European journal of nuclear medicine and molecular imaging》1997,24(10):1261-1267
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.
Received 19 April and in revised form 10 June 1997 相似文献
4.
T. Kobayashi F.A. Neethling S. Taniguchi Y. Ye M. Niekrasz E. Koren W.W. Hancock H. Takagi D.K.C. Cooper 《Xenotransplantation》1996,3(3):237-245
Abstract: We examined whether hyperacute rejection (HAR) of a discordant xenograft in a nonhuman primate model could be inhibited by the anticomplement agents, FUT-175 (FUT) and K76COOH (K76). The inhibitory effect of FUT and K76 on baboon sera was studied in vitro by i) complement-mediated hemolysis of sheep erythrocytes (by measuring serum CH50) and ii) cytotoxicity to cultured pig kidney (PK15) cells. The in vivo administration of FUT (at 0.2–25 mg/kg/h i.v. continuously) and K76 (50 mg/kg i.v. bolus) allowed evaluation of the serum levels of these drugs. Both FUT and K76 inhibited serum CH50 in a concentration-dependent manner. An enhanced effect was obtained by combining K76 with FUT therapy. High concentrations of FUT (>10-4 M) and K76 (>103 μxg/ml) were necessary to suppress serum CH50 to <5% of the normal level. However, PK15 cytotoxicity remained at >50% in the presence of i) 10-4 M of FUT, ii) 103 μg/ml of K76, and iii) 10-6 M of FUT + 103 μg/ml of K76. Pig heart transplantation (HTX) was performed in two baboons receiving FUT (1 mg/kg/h i.v. continuously) and K76 (at 200 mg/kg ×1 or 400 mg/kg + 200 mg/kg × 2 i.v, respectively). Cytotoxicity of the serum to PK15 cells at the time of HTX showed 39% and 1% cell death, respectively, in these two baboons, and the CH50 level was 1% (of control level) and 0%, respectively. Graft survival was 4.5 hours and 10 hours (with death of the baboon), respectively (compared with a mean of 29 minutes in control experiments). Both excised grafts showed typical features of hyperacute rejection. Immunopathological studies revealed deposition of C1q, C3d, C6, properdin, and Factor B, demonstrating that complement activation was not fully inhibited by FUT and K76. We conclude that i) FUT and K76 are indeed potent complement inhibitors, ii) the dosages of FUT and K76 necessary to suppress complement-mediated injury cannot be extrapolated from previously reported data obtained from serum CH50 levels, and iii) higher (possibly toxic) dosages will be required to inhibit complement activation completely. It seems unlikely that HAR will be prevented by these drugs alone, although they may be beneficial when combined with other forms of therapy. 相似文献
5.
TCP80 is an approximately 80kDa mammalian cytoplasmic protein that binds to a set of mRNAs and inhibits their translation in vitro and ex vivo. This protein has high sequence similarity to interleukin-2 enhancer-binding factors (NF90/ILF3) and the M-phase phosphoprotein (MPP4)/DRBP76. A 110kDa immunologic isoform of TCP80/NF90/MPP4/DRBP76, termed TCP110, also is present in cytoplasm and nuclei of many types of cells. A cDNA sequence coding for TCP110 was derived by 5(')RACE. The TCP110 sequence is identical to ILF3. The gene coding for TCP110/ILF3 mapped to human chromosome 19 and the gene organization was analyzed using TCP80 and TCP110/ILF3 cDNA sequences. The TCP/ILF3 gene spans >34.8kb and contains 21 exons. At least one alternatively spliced product involving exons 19-21 exists and predicts the formation of either TCP80 or TCP110/ILF3. However, the functional relationships of TCP80 and TCP110/ILF3 required elucidation. The metabolic turnover rates and subcellular distribution of TCP80 and TCP110/ILF3 during the cell cycle showed TCP80 to be relatively stable (t(1/2)=5 days) in the cytoplasmic compartment. In comparison, TCP110/ILF3 migrated between the cytoplasmic and nuclear compartments during the cell cycle. The TCP110 C-terminal segment contains an additional nuclear localizing signal that plays a role in its nuclear translocation. This study indicates that the multiple cellular functions, i.e., translation control, interleukin-2 enhancer binding, or cell division, of TCP/ILF3 are fulfilled by alternatively spliced isoforms. 相似文献
6.
de la Hera Antonio; Marston Wendy; Aranda Crisanto; Toribio Marie-Luisa; Martinez-A. Carlos 《International immunology》1989,1(5):471-478
Development of the T cell lineage is characterized by the homingof hematopoietic precursors to thymus, followed by their acquisitionof receptors for antigen. T cell receptors are ß or heterodimers associated with CD3 (TCR-CD3). Very early T cellprecursors in humans have been characterized as CD7+45+ cellswhich lack the T cell differentiation antigens CD1, CD2, CD3,CD4, and CD8. A phenotypically equivalent early thymocyte populationalso occurs in postnatal life, and we have previously shownthat interleukin 2 (IL2) promotes the development in vitro ofboth the ß and the T cells from these early thymocytes.Here we have analyzed the requirements of the induction of theIL2 pathway in early thymocytes, and their developmental potential.We show that: (I) thymic stromal cells, which are present inthymocyte suspensions, are necessary to induce the IL2 pathwayand the development of ß or T cell lineages fromearly thymocytes in vitro; and (II) when removed from the invivo environment, early thymocytes can develop in vitro intoTCR-CD3– cells of the natural killer (NK) lineage. Weconclude that CD7+45+, CD1–2–3–4–8–early thymocytes are multipotential progenitors that, at least,have the capacity to develop into ß or T cell andNK lineages. The analysis of the mechanisms of generation andselection of human T and NK cell diversity, not feasible inbone marrow cultures, is now possible. 相似文献
7.
目的综述脂肪来源干细胞(adipose-derived stem cells,ADSCs)在皮肤瘢痕防治领域的研究进展。方法广泛查阅相关文献,对 ADSCs 预防、治疗皮肤瘢痕形成的体外实验、动物实验及临床研究效果、可能机制以及优化 ADSCs 效果的生物材料进行综述。结果体外、体内实验及临床研究提示 ADSCs 参与皮肤创伤愈合全过程,可能通过减轻炎症反应、促进血管新生,调控 p38/MAPK、过氧化物酶体增殖物激活受体 γ 或 TGF-β1/Smads 等通路抑制(肌)成纤维细胞活性,减少胶原沉积,从而预防、治疗皮肤瘢痕。生物工程材料,如猪脂肪源基质水凝胶、猪小肠黏膜下层细胞外基质以及人工合成的聚羟基丁酸酯-羟基戊酸盐支架,均有可能进一步提高 ADSCs 防治皮肤瘢痕形成的效能。 结论ADSCs 在皮肤瘢痕防治研究中取得了显著进展,但临床应用途径仍待进一步研究。 相似文献
8.
目的探讨 O-C2 角、O-EA 角及 Oc-Ax 角对于枕颈融合术后患者发生吞咽困难的预测作用。方法以 2010 年 4 月—2019 年 5 月 114 例行枕颈融合术且符合选择标准的患者作为研究对象。其中男 54 例,女 60 例;年龄 14~76 岁,平均 50.6 岁。术后随访时间 13~122 个月,中位时间 60.5 个月。收集患者术前以及末次随访时颈椎侧位 X 线片,测量 O-C2 角、O-EA 角、Oc-Ax 角和 nPAS,并计算手术前后差值(dO-C2 角、dO-EA 角、dOc-Ax 角和 dnPAS)。根据术后是否出现吞咽困难,将患者分为吞咽困难组和无吞咽困难组。比较两组患者一般资料(年龄、性别、固定节段以及合并类风湿性关节炎、寰枢椎脱位及联合前路减压术患者比例)、影像学指标,分析 114 例患者 dO-C2 角、dO-EA 角、dOc-Ax 角与 dnPAS 相关性,比较 3 种影像学指标对枕颈融合术后吞咽困难发生的预测价值。结果术后 31 例发生吞咽困难,发生率为 27.2%。吞咽困难组和无吞咽困难组患者年龄、固定节段以及合并类风湿性关节炎、寰枢椎脱位及联合前路减压术患者比例比较,差异均无统计学意义(P>0.05);性别比较差异有统计学意义(χ2=7.940,P=0.005)。114 例患者术前与末次随访时 O-C2 角和 Oc-Ax 角比较,差异无统计学意义(P>0.05);O-EA 角和 nPAS 比较,差异有统计学意义(P<0.05)。吞咽困难组和无吞咽困难组患者术前 O-EA 角、Oc-Ax 角、nPAS 比较差异均无统计学意义(P>0.05),O-C2 角比较差异有统计学意义(t=2.470,P=0.016);末次随访时上述指标比较差异均有统计学意义(P<0.05)。两组患者 dO-EA 角、dOc-Ax 角、dO-C2 角、dnPAS 比较,差异均有统计学意义(P<0.05)。相关性分析显示,dO-C2 角、dO-EA 角、dOc-Ax 角均与 dnPAS 成正相关(P<0.05)。dO-C2 角≤−5°、术后 O-EA 角≤100°、术后 Oc-Ax 角≤65° 时均存在术后吞咽困难发生风险(P<0.05),其中 dO-C2 角≤−5° 时发生风险最大(OR=14.4)。 结论dO-C2 角、术后 O-EA 角、术后 Oc-Ax 角均可作为枕颈融合术后吞咽困难的预测指标,其中 dO-C2 角预测价值最大。 相似文献
9.
Imamura Hitoshi Maruyama Toru Okabe Hiroaki Shimada Hidekata Otagiri Masaki 《Pharmaceutical research》1994,11(4):566-570
We examined different fluorescent probes suitable for fluorometric determination of 1-acid glycoprotein (AGP) in serum. Quinaldine red (QR) was shown to bind strongly and selectively to AGP. Taking advantage of the enhanced fluorescence of QR in the presence of AGP, we developed a direct method for the determination of serum AGP without removal of other serum proteins such as albumin. AGP concentrations in serum of healthy volunteers and patients correlated well with results from the conventional single radial immunodiffusion (SRID) method (r = 0.93, slope = 1). The newly developed method is faster and has a larger analytical concentration range than the SRID method. This method can also be used to determine AGP in serum of experimental animals, and it can serve to monitor AGP serum concentrations for pharmacokinetic evaluation of basic drugs. 相似文献
10.