Bifunctional chelators are complexing agents that are used to construct target specific metalloradiopharmaceuticals. Bifunctional chelators have a second functionality that can covalently attach the ligand to the targeting moiety.
Bifunctional chelators are complexing agents that are used to construct target specific metalloradiopharmaceuticals. A targeted radiophamaceutical is built up from three major components: radionuclide, bifunctional chelator and the targeting molecule. Besides being chelating agents, bifunctional chelators have a second functionality that can covalently attach the ligand to the targeting moiety. These functional groups usually have a n electrophilic site that will react selectively and under mild conditions with the nucleophilic amino or thiol groups of the targeting vector. A linker between the bifunctional ligand and the targeting vector is sometimes used to modify the pharmacokinetics of the radiopharmaceutical. The linker can be a simple hydrocarbon chain to increase lipophiliocity, an enzymatically cleavable oligopeptide or polyethyleneglycol. One of the most commonly used bifunctionals is the bisanhydride of DTPA. NHS esters of chelating agets are very popular bifunctionals sine they are react with amino groups very selectively. Coupling agents like HBTU, HATU and DCC have been used to form active esters such as DOTA-NHS ester. Another class of very frequently used bifunctional chelators have benzyl isothiocyanato groups as the reactive moiety. P-isothiocyanatobenzyl DOTA and p-isothiocyanatobenzyl DTPA are the most widely used bifunctional DOTA and DTPA derivative. Selection of the bifunctional ligand depends on several factors. As complex stability is of major importance, the nature of the radionuclide is a determining factor. Metal complexes of acyclic chelators are low kinetically labile while complexes of macrocyclic chelators have high kinetic stability. Thus, for diagnostic applications, where the radiopharmaceutical clears out of the body in a few ours, acyclic bifunctional chelators may be satisfactory. For therapy however, when the radiopharmaceutical stays in the body for up to several days, macrocyclic bifunctionals are better suited.