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 Miller, George W. Sledge, Gary 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
Pages (from-to)753-760
Number of pages8
JournalNuclear Medicine and Biology
Volume30
Issue number7
DOIs
StatePublished - Oct 2003

Fingerprint

Matrix Metalloproteinase Inhibitors
Tumor Biomarkers
Positron-Emission Tomography
Esters
Carbon
Neoplasms
Interleukin-1
isovaleric acid
Nude Mice
Muscles
2-(4-(6-fluorohex-1-ynyl)benzenesulfonylamino)-3-methylbutyric acid
Injections
Solid Phase Extraction
Valine
Methylation

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

Cite this

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

In: Nuclear Medicine and Biology, Vol. 30, No. 7, 10.2003, p. 753-760.

Research output: Contribution to journalArticle

Zheng, Qi-Huang ; Fei, Xiangshu ; DeGrado, Timothy R. ; Wang, Ji Quan ; Stone, K. Lee ; Martinez, Tanya D. ; Gay, Dawn J. ; Baity, Winston L. ; Mock, Bruce H. ; Glick-Wilson, Barbara E. ; Sullivan, Michael L. ; Miller, Kathy ; Sledge, George W. ; Hutchins, Gary. / 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. In: Nuclear Medicine and Biology. 2003 ; Vol. 30, No. 7. pp. 753-760.
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title = "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",
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.",
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author = "Qi-Huang Zheng and Xiangshu Fei and DeGrado, {Timothy R.} and Wang, {Ji Quan} and Stone, {K. Lee} and Martinez, {Tanya D.} and Gay, {Dawn J.} and Baity, {Winston L.} and Mock, {Bruce H.} and Glick-Wilson, {Barbara E.} and Sullivan, {Michael L.} and Kathy Miller and Sledge, {George W.} and Gary Hutchins",
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TY - JOUR

T1 - 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

AU - Zheng, Qi-Huang

AU - Fei, Xiangshu

AU - DeGrado, Timothy R.

AU - Wang, Ji Quan

AU - Stone, K. Lee

AU - Martinez, Tanya D.

AU - Gay, Dawn J.

AU - Baity, Winston L.

AU - Mock, Bruce H.

AU - Glick-Wilson, Barbara E.

AU - Sullivan, Michael L.

AU - Miller, Kathy

AU - Sledge, George W.

AU - Hutchins, Gary

PY - 2003/10

Y1 - 2003/10

N2 - (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.

AB - (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.

KW - (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [ C]methyl ester

KW - Cancer biomarker

KW - Carbon-11

KW - Matrix metalloproteinase inhibitor

KW - Positron emission tomography

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