99mTc-labeling kinetics of four thiol-containing chelators and 2-hydrazinopyridine: Factors influencing their radiolabeling efficiency

The relative 99mTc-labeling efficiency of several potentially tetradentate thiol-containing chelators was studied by competing them with glucoheptonate in the [99mTc]glucoheptonate complex, and was compared to that of 2-hydrazinopyridine (HYPY), a model compound for HYNIC (hydrazinonicotinamide). The thiol-containing chelators in their unprotected forms include 4,5-bis(mercaptoacetamido)pentanoic acid (H4L1), N-[2-(mercapto)propionyl]glycylglycylglycine (H4L2), 2-(mercapto)ethylaminoacetyl-image-cysteine (H3L3), and image diethyl ester (H3L4). There are several factors that influence the labeling efficiency of a chelator. These include donor atoms, chelator concentration, and reaction conditions such as temperature and reaction time, and pH of the reaction media. In all the cases, higher chelator concentration produces better radiolabeling yields. Heating at 100°C for 30 min is required for the successful 99mTc-labeling of N2S2 diamidedithol (H4L1) and N3S triamidethiol (H4L2), while the N2S2 monoamide monoaminedithiol (H3L3) can be well labeled under milder conditions. For the N2S2 diaminedithiol (H3L4), the ligand exchange could be completed within 60 min at room temperature. It is clear that substitution of an amine-N for an amide-N enhances the rate of 99mTc-labeling. The reaction of HYPY with [99mTc]glucoheptonate was carried out by heating the reaction mixture at 50°C for 30 min under acidic conditions (pH 4–5). The radiolabeling efficiency of HYPY using glucoheptonate as coligand is better than that of H4L1-H3L3, and is comparable to that of H3L4. Therefore, NYNIC and diaminedithiols are the candidates of choice as bifunctional coupling agents in labeling small biologically active molecules with very high potency.