Synthesis, biodistribution and micro-PET imaging of a potential cancer biomarker carbon-11 labeled MMP inhibitor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [ 11C]methyl ester

Qi Huang Zheng, Xiangshu Fei, Timothy R. DeGrado, Ji Quan Wang, K. Lee Stone, Tanya D. Martinez, Dawn J. Gay, Winston L. Baity, Bruce H. Mock, Barbara E. Glick-Wilson, Michael L. Sullivan, Kathy D. Miller, George W. Sledge, Gary D. Hutchins

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Abstract

(2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [11C]methyl ester ([11C]FMAME), a novel carbon-11 labeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarker. [ 11C]FMAME was prepared by appropriate precursor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid (FMA), which was synthesized in six steps from (D)-valine in 71% chemical yield. This acid precursor was labeled by [11C]methyl triflate through O-[ 11C]methylation method under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compound in 40-55% radiochemical yield, based on 11CO2, decay corrected to end of bombardment, and 15-20 min synthesis time. The biodistribution of [11C]FMAME was determined at 30 min post IV injection in breast cancer animal models MCF-7 transfected with IL-1α implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [11C]FMAME in these tumors were 1.13% dose/g in MCF-7 transfected with IL-1α implanted mice and 1.37% dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.05 ± 0.29 (T/M, MCF-7's), 0.77 ± 0.20 (T/B, MCF-7's) and 0.99 ± 0.35 (T/M, MDA-MB-435), 1.44 ± 0.69 (T/B, MDA-MB-435), respectively. Pretreatment of MCF-7 transfected with IL-1α tumor-bearing mice with MMP inhibitor FMA had no effect on [ 11C]FMAME biodistribution. Likewise, pretreatment of MDA-MB-435 tumor-bearing mice with FMA also showed no effect on [11C]FMAME biodistribution. The micro-PET images were acquired for 15 min from a MCF-7 transfected with IL-1α tumor-bearing mouse or a MDA-MB-435 tumor-bearing mouse at 30 min post IV injection of 1 mCi of [11C]FMAME using a dedicated high resolution (<3 mm full-width at half-maximum) PET imaging system (Indy-PET II scanner). The initial dynamic micro-PET images of [ 11C]FMAME in a MCF-7 transfected with IL-1α tumor-bearing mouse during different time periods of 0-15, 15-30, 30-45 and 45-60 min were performed by Indy-PET II. The PET images clearly showed both tumors were visible with [11C]FMAME. These results suggest that the localization of [11C]FMAME in the tumor is mediated by non-specific processes, and the visualization of [11C]FMAME on the tumor using the Indy-PET II scanner is related to non-specific binding.

Original languageEnglish (US)
Pages (from-to)753-760
Number of pages8
JournalNuclear Medicine and Biology
Volume30
Issue number7
DOIs
StatePublished - Oct 2003

Keywords

  • (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [ C]methyl ester
  • Cancer biomarker
  • Carbon-11
  • Matrix metalloproteinase inhibitor
  • Positron emission tomography

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

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