A new, general synthetic route to multidentate N,S ligands for use in technetium-99m radiopharmaceuticals. Preparation of diamido disulfur, diamino dithiol, and tripodal N3S3 prototypes. Comparative biodistributions of [99mTcvO-DADS]- analogues which contain 5,5,5- and 5,7,5-membered chelate ring systems.
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 99mTc results in a single radiochemical product, or the expected number of stereoisomeric products. FAB MS analysis, using 99Tc, 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 substituents on the 7-membered ring give rise to a 99mTc 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 99mTc 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 99mTc radiopharmaceutical. The 99mTc labeling of the DADT analogues 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.
Stepniak-Biniakiewicz
D
D
Biomedical Chemistry Research Center, University of Cincinnati, Ohio 45221-0172.
Chen
B H
BH
Deutsch
E
E
D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D003959:Diamines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D005260:Female; D007553:Isotope Labeling / Q000379:methods; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013455:Sulfur; D014018:Tissue Distribution
D000577:Amides; D003959:Diamines; D008024:Ligands; D015609:Organotechnetium Compounds; D013438:Sulfhydryl Compounds; D013455:Sulfur