4-4-difluoro-4-bora-3a-4a-diaza-s-indacene and Fibrosarcoma

Since the processing activity of the matrix metalloproteinase MT1-MMP regulates various cellular functions such as motility, invasion, growth, differentiation and apoptosis, precise in vivo evaluation of MT1-MMP activity in cancers can provide beneficial information for both basic and clinical studies. For this purpose, we designed a cleavable Positron Emission Tomography (PET)/optical imaging probe consisting of BODIPY650/665 and polyethylene glycol (PEG) conjugated to opposite ends of MT1-MMP substrate peptides. We used in vitro and in vivo fluorescence experiments to select suitable substrate peptide sequences and PEG sizes for the MT1-MMP probes and obtained an optimized structure referred to here as MBP-2k. Radiofluorinated MBP-2k ([(18)F]MBP-2k) was then successfully synthesized via an (18)F-(19)F isotopic exchange reaction in BODIPY650/665. After intravenous injection into mice with xenografted tumors, [(18)F]MBP-2k showed significantly higher accumulation in HT1080 tumors with high MT1-MMP activity than in A549 tumors that have low MT1-MMP activity. Moreover, PET images showed better contrast in HT1080 tumors. These results show that [(18)F]MBP-2k can be used as a hybrid PET/optical imaging agent and is a promising probe for non-invasive monitoring of MT1-MMP activity in cancers. This probe may also efficiently combine targeted tumor imaging with image-guided surgery that could be beneficial for patients in the future.

Topics: Animals; Biomarkers, Tumor; Boron Compounds; Cell Line, Tumor; Fibrosarcoma; Fluorescent Dyes; Fluorine Radioisotopes; Heterografts; Humans; Injections, Intravenous; Lung Neoplasms; Male; Matrix Metalloproteinase 14; Mice, Inbred BALB C; Mice, Nude; Microscopy, Fluorescence; Optical Imaging; Peptides; Polyethylene Glycols; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; Substrate Specificity; Tissue Distribution