A NEW, GENERAL SYNTHETIC ROUTE TO MULTIDENTATE N,S LIGANDS FOR USE IN TC-99M RADIOPHARMACEUTICALS - PREPARATION OF DIAMIDO DISULFUR, DIAMINO DITHIOL, AND TRIPODAL N3S3 PROTOTYPES - COMPARATIVE BIODISTRIBUTIONS OF [99MTCVO-DADS]- ANALOGS WHICH CONTAIN 5,5,5-MEMBERED AND 5,7,5-MEMBERED CHELATE RING-SYSTEMS

被引:11
作者
STEPNIAKBINIAKIEWICZ, D
CHEN, BH
DEUTSCH, E
机构
[1] UNIV CINCINNATI,BIOMED CHEM RES CTR,CINCINNATI,OH 45221
[2] UNIV CINCINNATI,DEPT CHEM,CINCINNATI,OH 45221
关键词
D O I
10.1021/jm00080a011
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A new, versatile synthetic route to a variety of tetradentate N2S2 and hexadentate N3S3 ligands for use in technetium-99m radiopharmaceuticals has been developed. The key reaction employs 1-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline (EEDQ) for coupling an appropriate di- or triamine with S-protected thioglycolic acid. Selected DADS (diamido disulfur) and DADT (diamino dithiol) and analogues derived from ethanediamine-1,2 and butanediamine-1,4, as well as a tripodal N3S3 analogue, were synthesized in high yield. The labeling of DADS analogue ligands derived from butanediamine-1,4 (DADS-bn) with Tc-99m results in a single radiochemical product, or the expected number of stereoisomeric products. FAB MS analysis, using Tc-99, indicates that DADS-bn ligands form a tetradentate 5,7,5-membered ring chelate system with the monooxo Tc(V) core: [TcO-DAD-bn]. In rat biodistribution studies the DADS-en and DADS-bn complexes show very similar biological activity. Phenyl substitutents on the 7-membered ring give rise to a Tc-99m complex of increased lipophilicity, increased liver uptake, and minimal hepatobillary clearance. Thus, new classes of DADS ligand analogues which contain a 5,7,5-membered chelate ring system are readily synthesized and labeled with Tc-99m to form stable complexes. The presence of the 7-membered chelate ring allows for facile introduction of pendant groups into the ligand system, and thus for a ready route to control the biodistribution of the resulting Tc-99m radiopharmaceutical. The Tc-99m labeling of the DADT analgoues derived from butanediamine-1,4 provided to be erratic, despite the use of a variety of labeling techniques; the larger ring system of DADT-bn apparently does not favor the monooxo Tc(V) core and appears to generate a mixture of mono- and dioxo Tc(V) cores.
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页码:274 / 279
页数:6
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