MMP Inhibitor radiotracer [¹¹C]methyl‐CGS 27023A: A new pet breast cancer imaging agent

Abstract

Breast cancer is the most commonly diagnosed cancer of women and the second leading cause of cancer deaths among women. Experiments in animal models of breast cancer have shown that matrix metalloproteinase (MMP) inhibitors can significantly reduce the growth rate of both primary and secondary tumors and can block the process of metastasis.(l) MMPs are

Synthesis of MMP inhibitor radiotracer [11C]CGS 25966, a new potential pet tumor imaging agent

“…2 was hydrolyzed under acidic conditions with hydrochloride and trifluoroacetic acid (TFA) into its carboxylic acid and followed by coupling with O-(tert-butyl)hydroxylamine hydrochloride in the presence of N-[(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotrizole (HOBT) and N-methylmorphorine (NMM) to give t-butylated hydroxamic acid (3). 12,15,16 Treatment of 3 with aluminum chloride and ethanethiol in dichloromethane (DCM) unexpectedly removed two protecting groups methyl and t-butyl to give the O-desmethylated precursor of CGS 25966 (4).…”

“…In our previous work, [15][16][17] the carbon-11 labeling was focused on the labeling at the aminohydroxyl position of hydroxamic acid CGS 27023A 12 to prepare methylated CGS 27023A analogs. In this ongoing study, the carbon-11 labeling was focused on the labeling at the methoxyphenyl position of hydroxamic acid CGS 25966.…”

Molecular Imaging of Matrix Metalloproteinases In Vivo Using Small Molecule Inhibitors for SPECT and PET

“…Nevertheless, the authors described that the preparations of hydroxamic acids 12a and 12b were characterised by low radiochemical yields, long reaction times and complicated purification procedures that prevented a reliable routine production and further in vitro and in vivo evaluations [118,119]. These drawbacks could be circumvented by aiming at the alternative lead structure of a hydroxamic acid methylester.…”

Radionuclide Imaging of Tumor Angiogenesis

“…102,103 Then, research groups focused on the development of several PET-compatible, mainly 11 C-and 18 F-labeled, CGS 25966 and CGS 27023A derivatives. [104][105][106][107] Preclinical evaluation of these tracers was either not successful 108 or not published. 104,105 Recently, novel fluorinated MMPIs, based on the lead structures, CGS 25966 and CGS 27023A, were synthesized and the inhibition potencies of the compounds were evaluated in in vitro MMP inhibition assays for MMP2, 8, 9, and 13.…”

“…[104][105][106][107] Preclinical evaluation of these tracers was either not successful 108 or not published. 104,105 Recently, novel fluorinated MMPIs, based on the lead structures, CGS 25966 and CGS 27023A, were synthesized and the inhibition potencies of the compounds were evaluated in in vitro MMP inhibition assays for MMP2, 8, 9, and 13. With the exception of one compound, all fluorinated hydroxamates are still potent, broad-spectrum MMPIs (IC 50 ¼ 0.5-527 nM).…”