18F-fluorobenzoate-labeled cystine knot peptides for PET imaging of integrin αvβ6

Benjamin J. Hackel, Richard H. Kimura, Zheng Miao, Hongguang Liu, Ataya Sathirachinda, Zhen Cheng, Frederick T. Chin, Sanjiv S. Gambhir

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45 Scopus citations


Integrin αvβ6 is a cell surface receptor minimally expressed by healthy tissue but elevated in lung, colon, skin, ovarian, cervical, and pancreatic cancers. A molecular PET agent for integrin αvβ6 could provide significant clinical utility by facilitating both cancer staging and treatment monitoring to more rapidly identify an effective therapeutic approach. Methods: Here, we evaluated 2 cystine knot peptides, R01 and S02, previously engineered with a 3-6 nM affinity for integrin αvβ6, for 18F radiolabeling and PET imaging of BxPC3 pancreatic adenocarcinoma xenografts in mice. Cystine knot peptides were labeled with N-succinimidyl-4- 18Ffluorobenzoate and evaluated for binding affinity and serum stability. Peptides conjugated with 18F-fluorobenzoate (2-3 MBq) were injected via the tail vein into nude mice xenografted with BxPC3 (integrin αvβ6-positive) or 293 (integrin αvβ6-negative) tumors. Small-animal PET scans were acquired at 0.5, 1, and 2 h after injection. Ex vivo g-counting of dissected tissues was performed at 0.5 and 2 h. Results: 18F- fluorobenzoate peptides were produced in 93% (18F-fluorobenzoate-R01) and 99% (18F-fluorobenzoate-S02) purity. 18F- fluorobenzoate-R01 and 18Ffluorobenzoate- S02 had affinities of 1.1 ± 0.2 and 0.7 ± 0.4 nM, respectively, and were 87% and 94%, respectively, stable in human serum at 37°C for 2 h. 18F- fluorobenzoate-R01 and 18Ffluorobenzoate- S02 exhibited 2.3 ± 0.6 and 1.3 ± 0.4 percentage injected dose per gram (%ID/g), respectively, in BxPC3 xenografted tumors at 0.5 h (n 5 4-5). Target specificity was confirmed by low tumor uptake in integrin αvβ 6-negative 293 tumors (1.4 ± 0.6 and 0.5 ± 0.2 %ID/g, respectively, for 18F-fluorobenzoate-R01 and 18F- fluorobenzoate-S02; both P<0.05; n 5 3-4) and low muscle uptake (3.1 ± 1.0 and 2.7 ± 0.4 tumor to muscle for 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02, respectively). Small-animal PET data were corroborated by ex vivo g-counting of dissected tissues, which demonstrated low uptake in nontarget tissues with only modest kidney uptake (9.2 ± 3.3 and 1.9 ± 1.2 %ID/g, respectively, at 2 h for 18F- fluorobenzoate-R01 and 18Ffluorobenzoate- S02; n 5 8). Uptake in healthy pancreas was low (0.3% ± 0.1% for 18F-fluorobenzoate- R01 and 0.03% ± 0.01% for 18F-fluorobenzoate-S02; n 5 8). Conclusion: These cystine knot peptide tracers, in particular 18F-fluorobenzoate-R01, show translational promise for molecular imaging of integrin αvβ6 overexpression in pancreatic and other cancers.

Original languageEnglish (US)
Pages (from-to)1101-1105
Number of pages5
JournalJournal of Nuclear Medicine
Issue number7
StatePublished - Jul 1 2013


  • Cystine knot
  • Integrin αβ
  • Positron emission tomography


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