Synthesis of leukotriene B4 antagonists labeled with In-111 or Tc-99m to image infectious and inflammatory foci
Synthesis of leukotriene B4 antagonists labeled with In-111 or Tc-99m to image infectious and inflammatory foci
复制标题
DOI：
10.1021/jm050383h
复制
发表时间：
2005-10-06
影响因子：
7.3
通讯作者：
Harris, TD
中科院分区：
文献类型：
--
作者：
Broekema, M;van Eerd, JJEM;Harris, TD
在之前的研究中，我们证实了亲脂性tc -99m标记的LTB4拮抗剂1 （RP517）在兔感染灶中积累，但肝胆清除阻碍了腹部病变的成像。我们现在报道使用半胱酸作为药代动力学调节剂来改善1。二价LTB4拮抗剂17 （DPC11870-11）是一种与In-111放射性标记的DTPA偶联物。单价LTB4拮抗剂15 （BMS57868-88）和二价LTB4拮抗剂18 （BMS5786881）与双功能螯合剂HYNIC偶联，用Tc-99m进行放射性标记。这三种化合物用In-111或Tc-99m有效标记，具有较高的放射化学纯度和特异活性。在急性肌肉内大肠杆菌感染的新西兰大白兔中获得的扫描图像表明，所有药物都能清晰地看到脓肿，清除仅是肾脏。tc -99m标记的LTB4拮抗剂的生物分布受到与HYNIC螯合剂使用的共配体以及受体结合部分的单价或二价性质的影响。以三辛和异烟酸为配体，HYNIC与Tc-99m配位的单价HYNIC偶联物15的科学成像效果最好。
In previous studies we demonstrated that lipophilic Tc-99m-labeled LTB4 antagonist 1 (RP517) accumulated in infectious foci in rabbits, but hepatobiliary clearance hampered imaging of abdominal lesions. We now report the use of cysteic acid as a pharmacokinetic modifier to improve the water solubility and renal clearance of three hydrophilic analogues of 1. Divalent LTB4 antagonist 17 (DPC11870-11) is a DTPA conjugate for radiolabeling with In-111. Monovalent LTB4 antagonists 15 (BMS57868-88) and divalent LTB4 antagonist 18 (BMS5786881) are conjugated to bifunctional chelator HYNIC for radiolabeling with Tc-99m. The three compounds labeled efficiently with In-111 or Tc-99m with high radiochemical purity and specific activities. Scintigraphic images obtained in New Zealand White rabbits having acute intramuscular E. coli infection demonstrated that all agents were able to clearly visualize the abscess, and clearance was exclusively renal. The biodistribution of the Tc-99m-labeled LTB4 antagonists was affected by the coligands used with the HYNIC chelator and by the monovalent or divalent nature of the receptor binding moiety. The best scintigraphic images were obtained with monovalent HYNIC conjugate 15 using tricine and isonicotinic acid as coligands with HYNIC for coordination with Tc-99m.