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

(2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [C-11]methyl ester ([C-11]FMAME), a novel carbon-11 labeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarker. [C-11]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 [C-11]methyl triflate through O-[C-11]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 (CO2)-C-11, decay corrected to end of bombardment, and 15-20 min synthesis time. The biodistribution of [C-11]FMAME was determined at 30 min post IV injection in breast cancer animal models MCF-7 transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [C-11]FMAME in these tumors were 1.13% dose/g in MCF-7 transfected with IL-1alpha 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-1alpha tumor-bearing mice with MMP inhibitor FMA had no effect on [C-11]FMAME biodistribution. Likewise, pretreatment of MDA-MB-435 tumor-bearing mice with FMA also showed no effect on [C-11]FMAME biodistribution. The micro-PET images were acquired for 15 min from a MCF-7 transfected with IL-1alpha tumor-bearing mouse or a MDA-MB-435 tumor-bearing mouse at 30 min post IV injection of 1 mCi of [C-11]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 [C-11]FMAME in a MCF-7 transfected with IL-1 alpha 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 [C-11]FMAME. These results suggest that the localization of [C-11]FMAME in the tumor is mediated by non-specific processes, and the visualization of [C-11]FMAME on the tumor using the Indy-PET II scanner is related to non-specific binding. (C) 2003 Elsevier Inc. All rights reserved.