Design, synthesis, and initial evaluation of a high affinity positron emission tomography probe for imaging matrix metalloproteinases 2 and 9.

Abstract

The activity of matrix metalloproteinases (MMPs) is elevated locally under many pathological conditions. Gelatinases MMP2 and MMP9 are of particular interest because of their implication in angiogenesis, cancer cell proliferation and metastasis, and atherosclerotic plaque rupture. The aim of this study was to identify and develop a selective gelatinase inhibitor for imaging active MMP2/MMP9 in vivo. We synthesized a series of N-sulfonylamino acid derivatives with low to high nanomolar inhibitory potencies. (R)-2-(4-(4-Fluorobenzamido)phenylsulfonamido)-3-(1H-indol-3-yl)propanoic acid (7) exhibited the best in vitro binding properties: MMP2 IC50 = 1.8 nM, MMP9 IC50 = 7.2 nM. Radiolabeling of 7 with no carrier added (18)F-radioisotope was accomplished starting from iodonium salts as precursors. The radiochemical yield strongly depended on the iodonium counteranion (ClO4(-) > Br(-) > TFA(-) > tosylate). (18)F-7 was obtained in up to 20% radiochemical yield (decay corrected), high radiochemical purity, and >90 GBq/μmol specific radioactivity. The radiolabeled compound showed excellent stability in vitro and in mice in vivo.

• Authors: Svetlana V Selivanova, Timo Stellfeld, Tobias K Heinrich, Adrienne Müller, Stefanie D Krämer, P August Schubiger, Roger Schibli, Simon M Ametamey, Bernhard Vos, Jörg Meding, Marcus Bauser, Joachim Hütter, Ludger M Dinkelborg
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 12 Pg. 4912-20 (Jun 27 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23688254 (Publication Type: Journal Article)

Chemical References

• Fluorine Radioisotopes
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Chemistry Techniques, Synthetic
• Drug Design
• Fluorine Radioisotopes
• Humans
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Mice
• Mice, Inbred C57BL
• Multimodal Imaging (methods)
• Positron-Emission Tomography
• Tomography, X-Ray Computed