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.

New matrix metalloproteinase inhibitors based on γ-fluorinated α-aminocarboxylic and α-aminohydroxamic acids

“…[24][25][26][27] From both compounds radiolabelled analogues have been synthesized bearing the radionuclide [ 123/125 I], [ 18 F] or [ 11 C], respectively, that showed promising results in molecular imaging via SPECT and PET studies. 4,25,[28][29][30][31][32] All of the existing fluorinated analogues of such inhibitors carry the fluorine-containing substituent in an aromatic position.…”

Hypervalent aryliodine compounds as precursors for radiofluorination

“…Radiofluorination of an anisyl(aryl)iodonium tosylate precursor under conditions similar to those used for the labeling of flumazenil gave [ 18 F]fluoropalonosetron in a nonoptimized yield of 14% (Table , entry 7) . By contrast, a matrix metalloproteinase radioligand having a carboxamido group in para orientation to fluorine was radiofluorinated in 2 steps from a protected precursor, in which the initial radiofluorination yield was 70% (Table , entry 8) …”

“…125 By contrast, a matrix metalloproteinase radioligand having a carboxamido group in para orientation to fluorine was radiofluorinated in 2 steps from a protected precursor, in which the initial radiofluorination yield was 70% ( Table 3, entry 8). 128 In some cases, spectator groups other than 4-anisyl or 2-thienyl have been used successfully. Although the phenyl group is not the most effective spectator group for achieving high chemoselectivity in radiofluorination, aryl(phenyl)iodonium salts can still be quite attractive as precursors to radiotracers because of their relative ease of synthesis from commercially available Koser's reagent.…”

Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging

“…47 What is more, the counteranion of the diaryliodonium salt was found to significantly influence radiochemical yield (RCY). 56,57 Therefore, we chose to synthesize anisyl-and mesitylpalonosetron iodonium salts, in order to direct we utilized a reversed-phase HPLC ion-exchange protocol 57 to ensure generation of defined iodonium salts.…”