Early results in the irrational design of new bifunctional chelators

Abstract

Early Results in the Irrational Design of New Bifunctional Chelators BACKGROUND. The development of a simple route for the synthesis of the N-F. Chang, Ph.D. hydroxysuccinimide (NHS) ester of S-acetyl-protected mercaptoacetyltriglycine M. Rusckowski, Ph.D. (MAG 3 ) has opened the possibility of preparing novel bifunctional N 3 S chelators Timothy Qu, Ph.D.for technetium-99m ( 99m Tc) and other radionuclides. In particular, the synthesis Donald J. Hnatowich, Ph.D.may be applied to a vast number of tripeptides in place of triglycine, to provide a ''library'' of bifunctional N 3 S chelators, each with unique properties related to Department of Nuclear Medicine, University of the particular amino acid residues within each tripeptide. METHODS. The authors have synthesized by this simple route the NHS esters of Massachusetts.four N 3 S chelators by reacting NHS-S-acetylthioglycolic acid with ala-gly-gly, phegly-gly, pro-gly-gly, and ser-ser-ser, in addition to gly-gly-gly. Each bifunctional chelator was conjugated to biocytin as a model primary amine and radiolabeled with 99m Tc. The properties of the four chelators were compared with MAG 3 with respect to the stability of the label in saline and serum, the extent of serum protein binding, and the instability to cysteine challenge. RESULTS.A range of values was observed. Labeled mercaptoacetyltriserine showed stability towards transchelation to cysteine similar to that of MAG 3 as well as lower serum protein binding; labeled mercaptoacetylalanyldiglycine showed slightly higher serum protein binding than labeled MAG 3 but greater stability to cysteine challenge. CONCLUSIONS.The authors concluded that this simple synthesis and evaluation scheme may be used to prepare and screen a large library of bifunctional chelators for those with useful properties.

Therapeutic Radiopharmaceuticals

“…Significant advances have been made over the past decade in the development of promising radiolabeled agents that have been shown to be effective for treatment of human cancers. 11,38,40,43,50,220 As a result of these efforts, several new therapeutic radiopharmaceuticals that selectively target cancer cells in vivo are being evaluated in FDA-approved phase II and III clinical trials.…”

“…While considerable efforts have been devoted to the development of new magic bullets, none have received approval by the FDA (other than 131 I-sodium iodide) for routine use as therapeutic radiopharmaceuticals. Significant advances have been made over the past decade in the development of promising radiolabeled agents that have been shown to be effective for treatment of human cancers. ,,,,, As a result of these efforts, several new therapeutic radiopharmaceuticals that selectively target cancer cells in vivo are being evaluated in FDA-approved phase II and III clinical trials.…”

Potential Technetium Small Molecule Radiopharmaceuticals

“…Four tripeptide variations on N -hydroxysuccinimide (NHS) modified MAG 3 have been synthesized and evaluated in a simple scheme as bifunctional chelation agents for 99m Tc . Each of the bifunctional chelates prepared were conjugated to biocytin, a primary amine, complexed with 99m Tc, and evaluated for in vitro stability.…”

“…73 Four tripeptide variations on N-hydroxysuccinimide (NHS) modified MAG 3 have been synthesized and evaluated in a simple scheme as bifunctional chelation agents for 99m Tc. 74 Each of the bifunctional chelates prepared were conjugated to biocytin, a primary amine, complexed with 99m Tc, and evaluated for in vitro stability. The authors suggest that their methodology might be used to screen a large library of bifunctional chelating agents for the desired properties as a chelate for 99m Tc.…”

Structural characterisation and bioconjugation of an active ester containing oxorhenium(V) complex incorporating a thioether donor

“…These include the large group of N 2 S 2 ligands such as diaminedithiols, 3 monoamidemonoaminedithiols, 4 diamidedithiols, 4,5 and the N 3 S triamidethiols. 6 Other examples are propylene amines (PnAO), 7 tetraamines, 8 boronic adducts of technetium dioximes (BATO's), 9 and hydrazinonicotinamides (HYNIC). 10 Some comparative reviews are available.…”