title: 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.affiliation: Department of Radiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. qzheng@iupui.edu
authors.forename: Qi Huang
authors.initials: QH
authors.lastname: Zheng
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Fei
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Ji Quan
authors.initials: JQ
authors.lastname: Wang
authors.forename: K Lee
authors.initials: KL
authors.lastname: Stone
authors.forename: Tanya D
authors.initials: TD
authors.lastname: Martinez
authors.forename: Dawn J
authors.initials: DJ
authors.lastname: Gay
authors.forename: Winston L
authors.initials: WL
authors.lastname: Baity
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hutchins
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D045744:Cell Line, Tumor; D006877:Hydroxamic Acids / Q000737:chemistry / Q000493:pharmacokinetics*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009928:Organ Specificity; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C490456:2-(4'-methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid; D014408:Biomarkers, Tumor; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C490459:N-hydroxy-2-(((4'-methoxyphenyl)sulfonyl)benzylamino)-3-methylbutanamide; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D020782:Matrix Metalloproteinases; D014633:Valine