Facile Synthesis of Gd-DO3A-EA Conjugated with DTPA: A Novel Calcium Dependent MR Contrast Agent

‘Smart’ contrast agents (CA) exhibit dynamic and reversible modulation of their relaxivity by specific physiological or biochemical triggers such as changes in pH, Ca concentration or enzymatic activity (1-3). The extracellular concentration of Ca plays important role in physiological and pathological processes in the nervous system. This led to the designing of a chelating system in which relaxivity is influenced as a function of Ca concentration by changing coordination number around the paramagnetic metal ion. We synthesized a novel bifunctional bismacrocycle [Gd-(DO3A-DTPADO3A); Fig.] based on DO3A-EA [{4,7-Bis-carboxymethyl-10-(2-aminoethyl)-1,4,7,10-tetraazacyclododec-1-yl}-acetic acid] coupled to DTPA-bis-anhydride via a flexible alkyl spacer to form the amide linkages. The overall yield of the four step synthesis starting from cyclen was 54%. This gadolinium-based agent has two limiting conformational states with different Ca concentrations. It is hypothesized that in the absence of Ca, the carboxylates of the DTPA ligand interact with the Gd ions which were held in DO3A, but in the presence of Ca, these carboxylates rearrange to chelate Ca thereby allowing water to bind directly to Gd. N N N