The method to synthesize a high affinity muscarinic receptor antagonist (R,S)I-QNB[(R)-(-)-1-azabicyclo [2,2,2]oct-3-yl-(S)-(+)-α-hydroxy-α-(4-[127I]iodophenyl)-α-phenyl acetate] from 4-nitrobenzophenone with impro...The method to synthesize a high affinity muscarinic receptor antagonist (R,S)I-QNB[(R)-(-)-1-azabicyclo [2,2,2]oct-3-yl-(S)-(+)-α-hydroxy-α-(4-[127I]iodophenyl)-α-phenyl acetate] from 4-nitrobenzophenone with improvement compared to literatures was reported in this article. IR, MS and 1HNMR characterized the final product. (R,S)131I-QNB was prepared using Cu(I) assisted iodine exchange labeling, and showed by TLC that the radiolabeling yield(RLY) was over 80%, and radiochemical purity(RCP) was over 95%. Stability of the labeled compound was also determined. It was found that (R,S)131I-QNB dried by nitrogen blowing can stay at 4-10℃ for a week without change of RCP.展开更多
Background The liver manifestations of Alagille syndrome(ALGS)are highly variable,and factors affecting its prognosis are poorly understood.We asked whether the composition of bile acids in ALGS patients with good cli...Background The liver manifestations of Alagille syndrome(ALGS)are highly variable,and factors affecting its prognosis are poorly understood.We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers.Methods Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age.A good prognosis was defined as survival with native liver and total bilirubin(TB)<85.5 μmol/L,while a poor prognosis was defined as either liver transplantation,death from liver failure,or TB ≥ 85.5 μmol/L at the last follow-up.Results We found that the concentrations of two poly-hydroxylated bile acids,tauro-2β,3α,7α,12α-tetrahydroxylated bile acid(THBA)and glyco-hyocholic acid(GHCA),were significantly increased in patients with good prognosis compared to those with poor prognosis[area under curve(AUC)=0.836 and 0.782,respectively]in the discovery cohort.The same trend was also observed in the molar ratios of GHCA to glyco-chenodeoxycholic acid(GCDCA)and tetrahydroxylated bile acid(THCA)to tauro-chenodeoxycholic acid(TCDCA)(both AUC=0.836).A validation cohort confirmed these findings.Notably,tauro-2β,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00%(92.31%sensitivity and 83.33%specificity);GHCA at>607.69 nmol/L was associated with native liver survival[hazard ratio:13.03,95%confidence interval(CI):(2.662-63.753),P=0.002].Conclusions We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients.Enhanced hydroxylation of bile acids may result in better clinical outcomes.展开更多
基金Foundation for Outstanding Young Members of Health Ministry in China(9925)
文摘The method to synthesize a high affinity muscarinic receptor antagonist (R,S)I-QNB[(R)-(-)-1-azabicyclo [2,2,2]oct-3-yl-(S)-(+)-α-hydroxy-α-(4-[127I]iodophenyl)-α-phenyl acetate] from 4-nitrobenzophenone with improvement compared to literatures was reported in this article. IR, MS and 1HNMR characterized the final product. (R,S)131I-QNB was prepared using Cu(I) assisted iodine exchange labeling, and showed by TLC that the radiolabeling yield(RLY) was over 80%, and radiochemical purity(RCP) was over 95%. Stability of the labeled compound was also determined. It was found that (R,S)131I-QNB dried by nitrogen blowing can stay at 4-10℃ for a week without change of RCP.
基金Key Research and Development Program of China(No.2021YFC 2,700,800 to J-S W.National Natural Science Foundation of China(No.81741056 to WJS)National Natural Science Foundation of China(No.81873543 to WJS)Natural Science Foundation of Shanghai(20YF1402900 to T L).
文摘Background The liver manifestations of Alagille syndrome(ALGS)are highly variable,and factors affecting its prognosis are poorly understood.We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers.Methods Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age.A good prognosis was defined as survival with native liver and total bilirubin(TB)<85.5 μmol/L,while a poor prognosis was defined as either liver transplantation,death from liver failure,or TB ≥ 85.5 μmol/L at the last follow-up.Results We found that the concentrations of two poly-hydroxylated bile acids,tauro-2β,3α,7α,12α-tetrahydroxylated bile acid(THBA)and glyco-hyocholic acid(GHCA),were significantly increased in patients with good prognosis compared to those with poor prognosis[area under curve(AUC)=0.836 and 0.782,respectively]in the discovery cohort.The same trend was also observed in the molar ratios of GHCA to glyco-chenodeoxycholic acid(GCDCA)and tetrahydroxylated bile acid(THCA)to tauro-chenodeoxycholic acid(TCDCA)(both AUC=0.836).A validation cohort confirmed these findings.Notably,tauro-2β,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00%(92.31%sensitivity and 83.33%specificity);GHCA at>607.69 nmol/L was associated with native liver survival[hazard ratio:13.03,95%confidence interval(CI):(2.662-63.753),P=0.002].Conclusions We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients.Enhanced hydroxylation of bile acids may result in better clinical outcomes.
