Cai Lisheng, Chin Frederick T, Pike Victor W, Toyama Hiroshi, Liow Jeih-San, Zoghbi Sami S, Modell Kendra, Briard Emmanuelle, Shetty H Umesha, Sinclair Kathryn, Donohue Sean, Tipre Dnyanesh, Kung Mei-Ping, Dagostin Claudio, Widdowson David A, Green Michael, Gao Weiyi, Herman Mary M, Ichise Masanori, Innis Robert B
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
J Med Chem. 2004 Apr 22;47(9):2208-18. doi: 10.1021/jm030477w.
This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.
本研究评估了用正电子发射断层扫描（PET）成像β-淀粉样蛋白斑块的试剂——（18）F标记的IMPY[6-碘-2-（4'-N，N-二甲基氨基）苯基咪唑并[1,2-a]吡啶]衍生物。放射性标记前体和参考化合物由市售起始原料经多达五步合成。IMPY的两个N-甲基中的一个被3-氟丙基（FPM-IMPY）或2-氟乙基（FEM-IMPY）取代。发现FPM-IMPY和FEM-IMPY对Abeta聚集体具有中等亲和力，K（i）分别为27±8和40±5 nM。开发了一种用于前体的（18）F-2-氟乙基化和（18）F-3-氟丙基化的“一锅法”。经衰变校正后的总放射化学产率为26-51%。在正常小鼠的PET实验中，静脉注射每种探针后，大脑中均有高放射性摄取：[(18)F]FEM-IMPY在1.2分钟时为6.4% ID/g，[(18)F]FPM-IMPY在0.8分钟时为5.7% ID/g。这些值与[(I23/I25)I]IMPY的值（2分钟时为7.2% ID/g）相似。注射[(18)F]FEM或[(18)F]FPM-IMPY后，在血浆和脑匀浆中均观察到极性和非极性放射性代谢物。与[(I23/I25)I]IMPY的单指数洗脱不同，两种氟化类似物的脑放射性洗脱是双相的，最初20分钟内有一个快速相，随后是一个慢得多的相。2小时时的残留脑放射性，可能代表被困在脑中的极性代谢物，[(18)F]FEM-IMPY为4.5% ID/g，[(18)F]FPM-IMPY为2.1% ID/g。还清楚地观察到[(18)F]氟化物在颅骨中有大量摄取。为了减缓[(18)F]FEM-IMPY的代谢，制备了一种用氘取代四个乙基氢的类似物。然而，D(4)-[(18)F]FEM-IMPY的脑摄取和清除与原型类似物相同。[(18)F]FEM-IMPY在恒河猴中的代谢明显比在小鼠中慢。用[(18)F]FEM-IMPY对人类阿尔茨海默病患者死后脑切片进行放射自显影显示，灰质中有高可置换摄取，白质中有低非特异性结合。本研究表明，IMPY衍生物在体内具有良好的脑药代动力学，对成像β-淀粉样蛋白斑块具有中等亲和力；然而，需要进一步改进以减少放射性代谢物、增加结合亲和力并降低亲脂性。
