A1 Refereed original research article in a scientific journal
Development of matrix metalloproteinase-targeted probes for lung inflammation detection with positron emission tomography
Authors: Kondo N, Temma T, Aita K, Shimochi S, Koshino K, Senda M, Iida H
Publisher: NATURE PUBLISHING GROUP
Publication year: 2018
Journal: Scientific Reports
Journal name in source: SCIENTIFIC REPORTS
Journal acronym: SCI REP-UK
Article number: ARTN 1347
Volume: 8
Number of pages: 10
ISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-018-19890-1
Abstract
As matrix metalloproteinases (MMPs), especially MMP-9 and MMP-12 are involved in the pathological processes associated with chronic obstructive pulmonary disease (COPD), we developed a novel radiofluorinated probe, F-18-IPFP, for MMPs-targeted positron emission tomography (PET). 18F-IPFP was designed by iodination of MMP inhibitor to enhance the affinity, and labelled with a compact prosthetic agent, 4-nitrophenyl 2-F-18-fluoropropionate (F-18-NFP). As a result, IPFP demonstratedthe highest affinity toward MMP-12 (IC50 = 1.5 nM) among existing PET probes. A COPD model was employed by exposing mice to cigarette smoke and the expression levels of MMP-9 and MMP-12 were significantly increased in the lungs. Radioactivity accumulation in the lungs 90 min after administration of F-18-IPFP was 4x higher in COPD mice than normal mice, and 10x higher than in the heart, muscle, and blood. Ex vivo PET confirmed the radioactivity distribution in the tissues and autoradiography analysis demonstrated that accumulation differences in the lungs of COPD mice were 2x higher than those of normal mice. These results suggest that F-18-IPFP is a promising probe for pulmonary imaging and expected to be applied to various MMP-related diseases for early diagnosis, tracking of therapeutic effects, and new drug development in both preclinical and clinical applications.
As matrix metalloproteinases (MMPs), especially MMP-9 and MMP-12 are involved in the pathological processes associated with chronic obstructive pulmonary disease (COPD), we developed a novel radiofluorinated probe, F-18-IPFP, for MMPs-targeted positron emission tomography (PET). 18F-IPFP was designed by iodination of MMP inhibitor to enhance the affinity, and labelled with a compact prosthetic agent, 4-nitrophenyl 2-F-18-fluoropropionate (F-18-NFP). As a result, IPFP demonstratedthe highest affinity toward MMP-12 (IC50 = 1.5 nM) among existing PET probes. A COPD model was employed by exposing mice to cigarette smoke and the expression levels of MMP-9 and MMP-12 were significantly increased in the lungs. Radioactivity accumulation in the lungs 90 min after administration of F-18-IPFP was 4x higher in COPD mice than normal mice, and 10x higher than in the heart, muscle, and blood. Ex vivo PET confirmed the radioactivity distribution in the tissues and autoradiography analysis demonstrated that accumulation differences in the lungs of COPD mice were 2x higher than those of normal mice. These results suggest that F-18-IPFP is a promising probe for pulmonary imaging and expected to be applied to various MMP-related diseases for early diagnosis, tracking of therapeutic effects, and new drug development in both preclinical and clinical applications.
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