Monitoring tumor response to linifanib therapy with SPECT/CT using the integrin αvβ3-targeted radiotracer 99mTc-3P-RGD2

J Pharmacol Exp Ther. 2013 Aug;346(2):251-8. doi: 10.1124/jpet.112.202622. Epub 2013 Jun 7.


The objective of this study was to determine the utility of (99m)Tc-3P-Arg-Gly-Asp (RGD2) single photon emission computed tomography (SPECT)/computed tomography (CT) for noninvasive monitoring of integrin αvβ3-expression response to antiangiogenic treatment with linifanib. Linifanib or vehicle therapy was carried out in female athymic nu/nu mice bearing U87MG glioma (high αvβ3 expression) or PC-3 prostate (low αvβ3 expression) tumors at 12.5 mg/kg twice daily. The average tumor volume was 180 ± 90 mm(3) the day prior to baseline SPECT/CT. Longitudinal (99m)Tc-3P-RGD2 SPECT/CT imaging was performed at baseline (-1 day) and days 1, 4, 11, and 18. Tumors were harvested at all imaging time points for histopathological analysis with H&E and immunohistochemistry. A significant difference in tumor volumes between vehicle- and linifanib-treated groups was observed after 4 days of linifanib therapy in the U87MG model. The percent injected dose (%ID) tumor uptake of (99m)Tc-3P-RGD2 peaked in the vehicle-treated group at day 11, while the %ID/cm(3) tumor uptake decreased slowly over the whole study period. During the first 2 days of linifanib treatment, a rapid decrease in both %ID/cm(3) tumor uptake and tumor/muscle ratios of (99m)Tc-3P-RGD2 was observed, followed by a slow decrease until day 18. No decrease in tumor uptake of (99m)Tc-3P-RGD2 or tumor volume was observed for either treatment group in the PC-3 model. Changes in tumor vasculature were confirmed by histopathological H&E analysis and immunohistochemistry. Longitudinal imaging using (99m)Tc-3P-RGD2 SPECT/CT may be a useful tool for monitoring the downstream biologic effects of linifanib therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Biomarkers, Tumor / metabolism
  • Dimerization
  • Female
  • Glioma
  • Humans
  • Indazoles / therapeutic use*
  • Integrin alphaVbeta3 / metabolism*
  • Male
  • Mice
  • Mice, Nude
  • Multimodal Imaging
  • Oligopeptides*
  • Organotechnetium Compounds
  • Peptides, Cyclic
  • Phenylurea Compounds / therapeutic use*
  • Positron-Emission Tomography
  • Prostatic Neoplasms
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Radiopharmaceuticals*
  • Technetium
  • Tomography, X-Ray Computed
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • Indazoles
  • Integrin alphaVbeta3
  • Oligopeptides
  • Organotechnetium Compounds
  • Peptides, Cyclic
  • Phenylurea Compounds
  • Radiopharmaceuticals
  • technetium 99m (HYNIC-3PRGD(2))(tricine)(TPPTS)
  • Technetium
  • arginyl-glycyl-aspartic acid
  • linifanib
  • Protein-Tyrosine Kinases