A Gadolinium Chelate for Detection of β-Glucuronidase: A Self-Immolative Approach

New classes of physiologically responsive magnetic resonance (MR) contrast agents are being developed that are activated by enzymes, secondary messengers, pH, and temperature. To this end, we have prepared a new class of enzyme-activated MR contrast agents using a self-immolative mechanism and investigated the properties of these agents using novel in vitro assays. We have synthesized in nine steps a Gd(III) agent 1 that is activated by the oncologically significant β-glucuronidase. 1 consists of Gd(III)DO3A (DO3A = 1,4,7-tricarboxymethylene-1,4,7,10-tetraazacyclododecane) bearing a pendant β-glucuronic acid moiety connected by a self-immolative linker to the macrocycle. LC−MS analysis reveals that 1 is enzymatically processed as predicted by bovine liver β-glucuronidase, generating 2-aminoethylGdDO3A, 2. Compound 2 was prepared independently in a four-step synthetic procedure. Complex 1 displays a decrease in relaxivity upon titration with bicarbonate anion. The relaxivity increases when 1 is converted t...