Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

Abstract

Imaging techniques for detection of molecular and cellular processes that precede or accompany lung diseases are needed. Matrix metalloproteinases (MMPs) play key roles in the development of pulmonary pathology. Objectives Investigate the feasibility of in vivo MMP-targeted molecular imaging for detection of lung inflammation and remodeling. Methods Lung-specific IL-13 transgenic [Club cell 10-kDa protein (CC10)-IL-13Tg)] mice, and wild type (WT) littermates were used in this study. Lung structure, gene expression, and MMP activity were assessed by histology, real-time reverse transcription polymerase chain reaction, Western blot and zymography. MMP activation was imaged by in vivo micro single-photon emission computed tomography (SPECT)/CT followed by ex vivo planar imaging. Signal specificity was addressed using a control tracer. The correlation between in vivo MMP signal and gene expression was addressed. Results CC10-IL-13Tg mice developed considerable pulmonary tissue remodeling and inflammation. CD68, MMP-12 and MMP-13 were significantly higher in CC10-IL-13Tg lungs. On in vivo microSPECT/CT and ex vivo planar images, the MMP signal was significantly higher in the lungs of CC10-IL-13Tg mice than WT animals. Furthermore, a non-binding analog tracer showed significantly lower accumulation in CC10-IL-13Tg lungs relative to the specific tracer. There was a significant correlation between microSPECT/CT-derived MMP signal and CD68 expression in the lungs (r = 0.70, P < 0.01). Conclusions MicroSPECT/CT-based MMP-targeted imaging of the lungs is feasible and reflects pulmonary inflammation. If validated in humans, molecular imaging of inflammation and remodeling can potentially help early diagnosis and monitoring of the effects of therapeutic interventions in pulmonary diseases.

Preclinical Evaluation of RYM1, a Matrix Metalloproteinase–Targeted Tracer for Imaging Aneurysm

“…RP805 was labeled with 99m Tc, in the presence of 3,39,3$-phosphanetriyltris (benzenesulfonic acid) trisodium salt and tricine coligands in a Sn-free formulation, as previously described (7). RYM1 was similarly labeled with 99m Tc to give 99m Tc-RYM1 in a high radiochemical yield.…”

“…RP805 precursor was synthesized as described (7). The macrocyclic hydroxamate-based pan-MMP inhibitor RYM and its 6-hydrazinonicotinamide conjugate RYM1 were synthesized starting from an antisuccinic acid derivative, (2R,3S)-3-(tert-butoxycarbonyl)-2-iso-butylhex-5-enoic acid, in a 15-step reaction via a macrocyclic hydroxamic acid as a key intermediate (Supplemental Fig.…”

Development of matrix metalloproteinase-targeted probes for lung inflammation detection with positron emission tomography

“…However, 18 F-FDG also accumulates in macrophages, lymphocytes, and eosinophils, as well as structural cells within the lungs, so that increased 18 F-FDG uptake in the lungs reflects the integrated inflammatory response and cannot be used as a specific indicator of inflammation 20 . In contrast, MMPs are known to be diagnostic markers of COPD, and MMP inhibitors have been shown to be effective for COPD treatment in preclinical experiments 4 – 6 . Therefore, in vivo imaging of MMP expression could contribute to the diagnosis and treatment of COPD.…”

“…MMPs are a family of zinc-dependent proteinases that play important roles in degrading the extracellular matrix and tissue remodeling both in normal physiological states and in abnormal pathological processes. MMPs play a key role in pulmonary inflammation and are recognized as promising diagnostic and therapeutic targets in COPD 4 – 6 . Among the various subtypes of MMPs, MMP-12, a potent elastase, is an essential mediator of the pathophysiology of COPD 5 , 7 , 8 , and MMP-9 functions as an indicator of the clinical COPD stage 9 – 11 .…”

Playing slot to hitting the jackpot in molecular imaging: On probability of uncovering subcellular pathogenesis vs achieving clinical applicability

“…Besides a role in remodeling, MMP play an important role in various other cardiovascular diseases, including atherosclerosis, [23][24][25][26][27][28][29] calcific aortic valve disease, 30 aortic aneurysm formation, 31 and pulmonary inflammation. 32 Moreover, MMP also play a role in non-cardiac diseases, notably malignancy. 33 In the latter setting, MMP contribute to angiogenesis, tumor invasion, and metastasis, and considerable interest has developed in imaging MMP.…”