Researchers aimed to develop a potent MMP probe , specifically targeting MMP-12 and MMP-9, based on ML5 for noninvasive COPD imaging with PET . As attachment of the 18 F-fluorobenzoyl moiety Decreased the affinity of ML5 Toward MMP-12, we selected another prosthetic agent for radiofluorination, 4-nitrophenyl 2- Namely 18 F-fluoropropionate ( 18 F-NFP ) .
Pulmonary diseases including COPD are major causes of morbidity and mortality worldwide. COPD is a complex and heterogeneous condition requiring personalized medicine. COPD is an inflammatory disease caused by long-term inhalation exposure to noxious insults, mainly smoking, and characterized by irreversible airway limitation and accelerated decline of lung function .
Currently, COPD is diagnosed through clinical manifestations, spirometry , and anatomic imaging, and is limited by insufficient assessment of physiological alterations. Thus, development of in vivo molecular imaging methods is required to contribute to early diagnosis of COPD and evaluation of therapeutic interventions.
As matrix metalloproteinases (MMPs), especially MMP-9 and MMP-12 are involved in the pathological processes associated with chronic obstructive pulmonary disease (COPD), developed a novel radiofluorinated probe, 18 F-IPFP, for MMPs-targeted positron emission tomography ( PET )
18 F-IPFP was designed by iodination of MMP inhibitor to enhance the affinity, and labelled with a compact prosthetic agent, 18 F-NFP. As a result, IPFP demonstrated the highest affinity to MMP-12 (IC 50 = 1.5 nM) among existing PET probes. A COPD model was used by exposure to MMP-9 and MMP-12 levels of cigarette smoke and the expression levels were significantly increased in the lungs.
Radioactivity accumulation in the lungs 90 min after administration of 18 F-IPFP was 4 × higher in COPD than normal mice, and 10 × 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 2 × higher than those of normal mice.
These results suggest that 18 F-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.
This study also demonstrated a rational drug design for the development of short peptide-based probes. 18 F-IPFP is expected to be applied to various MMP-related diseases such as pulmonary inflammation, atherosclerosis, and cancer, for early diagnosis, tracking of therapeutic effects, and new drug development in both preclinical and clinical applications.