Novel Arginine-containing Macrocyclic MMP Inhibitors: Synthesis, (99m)Tc-labeling, and Evaluation

Matrix metalloproteinases (MMPs) are involved in tissue remodeling. Accordingly, MMP inhibitors and related radiolabeled analogs are important tools for MMP-targeted imaging and therapy in a number of diseases. Herein, we report design, synthesis, and evaluation of a new Arginine-containing macrocyclic hydroxamate analog, RYM, its hydrazinonicotinamide conjugate, RYM1 and (99m)Tc-labeled analog (99m)Tc-RYM1 for molecular imaging. RYM exhibited potent inhibition against a panel of recombinant human (rh) MMPs in vitro. RYM1 was efficiently labeled with (99m)TcO(4)(−) to give (99m)Tc-RYM1 in a high radiochemical yield and high radiochemical purity. RYM1 and its decayed labeling product displayed similar inhibition potencies against rhMMP-12. Furthermore, (99m)Tc-RYM1 exhibited specific binding with lung tissue from lung-specific interleukin-13 transgenic mice, in which MMP activity is increased in conjunction with tissue remodeling and inflammation. The results support further development of such new water-soluble Arginine-containing macrocyclic hydroxamate MMP inhibitors for targeted imaging and therapy.