Development of Novel Nuclear Medical Imaging Probes for Quantification of Matrix Metalloproteinases in Diseases

Abstract

Matrix metalloproteinases (MMPs) regulate various cellular functions, such as motility, invasion, differentiation, and apoptosis. Precise in vivo quantification of MMPs in disease can provide beneficial information for both basic and clinical research studies. To this end, various types of probes have been developed for imaging MMPs in vivo. In this review, representative MMP-targeted probes, such as binding probes and activatable probes, are outlined, including highlights of our own research. In addition, strategies for the development of probes that apply "theranostics," a concept that integrates therapy and diagnostics, are elucidated with reference to [18F]IPFP, a new probe developed in our laboratory. [18F]IPFP was prepared by iodination of a known MMP inhibitor to enhance its affinity and labeled with the compact prosthetic agent 4-nitrophenyl 2-[18F]fluoropropionate ([18F]NFP) for MMP-targeted positron-emission tomography (PET) and other therapeutic properties. IPFP demonstrated high inhibitory activity toward MMP-12 (IC50 value=1.5 nM). Radioactivity accumulation in the lungs 90 min after administration of [18F]IPFP was 4-fold higher in chronic obstructive pulmonary disease (COPD) mice overexpressing MMPs compared with normal mice. Ex vivo PET confirmed the radioactivity distribution in tissues, and autoradiography analysis demonstrated accumulation differences between COPD and normal mice. Consequently, [18F]IPFP showed potent inhibitory activities against MMPs and suitable pharmacokinetics for imaging pulmonary disease. Thus, [18F]IPFP is a promising theranostic probe for pulmonary disease and is expected to be applied to various other MMP-related diseases. Strategies for MMP probe development introduced in this review are anticipated to lead to the development of superior imaging probes in the future.