Comparative studies of potential cancer biomarkers carbon-11 labeled MMP inhibitors (S)-2-(4'-[11C]methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid and N-hydroxy-(R)-2-[[(4'-[11C]methoxyphenyl)sulfonyl]benzylamino]-3-methylbutanamide.

Abstract

(S)-2-(4'-[11C]methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid ([11C]MSMA) and N-hydroxy-(R)-2-[[(4'-[11C]methoxyphenyl)sulfonyl]benzylamino]-3-methylbutanamide ([11C]CGS 25966), carbon-11 labeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarkers. [11C]MSMA was prepared by appropriate precursor (S)-2-(4'-hydroxybiphenyl-4-sulfonylamino)-3-methylbutyric acid tert-butyl ester, which was synthesized in eight steps from amino acid (L)-valine in 39.4% chemical yield. This precursor was labeled by [11C]methyl triflate through O-[11C]methylation method at the hydroxyl position of biphenol under basic conditions, followed by a quick acid hydrolysis and isolated by solid-phase extraction (SPE) purification to produce pure target compound [11C]MSMA in 35-55% radiochemical yield, based on 11CO2, decay corrected to end of bombardment (EOB), and 20-25 min synthesis time. [11C]CGS 25966 was prepared in our previous work starting from amino acid (D)-valine. The biodistribution of [11C]MSMA and [11C]CGS 25966 were determined at 45 min post iv injection in breast cancer animal models MCF-7's transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [11C]MSMA and [11C]CGS 25966 in these tumors were 0.95 and 0.42%dose/g in MCF-7's transfected with IL-1alpha implanted mice, 0.98 and 1.53%dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.21 and 1.09 (T/M, MCF-7's), 0.99 and 0.84 (T/B, MCF-7's), 1.38 and 1.27 (T/M, MDA-MB-435), 1.27 and 1.95 (T/B, MDA-MB-435), respectively. The micro-PET images of [11C]MSMA and [11C]CGS 25966 in both breast cancer athymic mice were acquired for 15 min from a MCF-7's transfected with IL-1alpha and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, Indy-PET II scanner, developed in our laboratory, which showed both tumors were invisible with both tracers. The results were compared. From our results, we concluded that both [11C]MSMA and [11C]CGS 25966 might be unsuitable as PET tracers for cancer imaging.

• Authors: Qi Huang Zheng, Xiangshu Fei, Xuan Liu, Ji Quan Wang, K Lee Stone, Tanya D Martinez, Dawn J Gay, Winston L Baity, Kathy D Miller, George W Sledge, Gary D Hutchins
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 31 Issue 1 Pg. 77-85 (Jan 2004) ISSN: 0969-8051 [Print] United States
• PMID: 14741572 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2-(4'-methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid
• Biomarkers, Tumor
• Hydroxamic Acids
• Matrix Metalloproteinase Inhibitors
• N-hydroxy-2-(((4'-methoxyphenyl)sulfonyl)benzylamino)-3-methylbutanamide
• Radiopharmaceuticals
• Sulfonamides
• Matrix Metalloproteinases
• Valine

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (diagnostic imaging, metabolism)
• Cell Line, Tumor
• Hydroxamic Acids (chemistry, pharmacokinetics)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (chemistry, metabolism)
• Mice
• Organ Specificity
• Radionuclide Imaging
• Radiopharmaceuticals (chemistry, pharmacokinetics)
• Sulfonamides (chemistry, pharmacokinetics)
• Tissue Distribution
• Valine (analogs & derivatives, chemistry, pharmacokinetics)