A gadolinium triacetic monoamide DOTA derivative with a methanethiosulfonate anchor group. Relaxivity properties and conjugation with albumin and thiolated particles

The gadolinium(III) complex with a new DOTA-based ligand bearing a methanethiosulfonate group (MTS) was synthesized and its relaxivity properties were investigated. MTS-ADO3A is a triacid DOTA derivative with an amide arm substituted by an ethylmethanethiosulfonate function. This ligand was obtained in two steps: tri-tert-butyl 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate was reacted with S-(2-aminoethyl)methanesulfonothioate and the tert-butyl groups were removed with trifluoroacetic acid. The Gd(III) MTS–ADO3A complex readily formed disulfide bonds with albumin (BSA) in its native and reduced forms and with thiolated silica particles. Four- to five-fold relaxivity increases at 20 MHz were measured on the isolated adducts. The EuMTS-ADO3A chelate was found to be monohydrated by fluorescence and the relaxivity parameters of the Gd(III) complex were obtained by 17O NMR and by measuring the nuclear magnetic relaxation dispersion between 0.01 and 80 MHz. The water exchange time τm is increased upon forming disulfide bonds with macromolecules and particles and the relaxivity gains of all the complexes are limited by the τm factor. Forming covalent or hydrophobic/electrostatic bonds with BSA seems to bring about similar relaxivity changes but the covalent BSA adducts can be isolated and their properties can be directly studied. The addition of dithiothreitol or glutathione leads to the removal of the metal chelates from the macromolecules, as indicated by the relaxation times reverting to their values before binding. It is thus expected that the chelate will stay in the body long enough for imaging but will still be excreted through the kidneys.