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

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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
Volume54
Issue number7
DOIs
StatePublished - Jul 1 2013

Keywords

  • Cystine knot
  • Integrin αβ
  • Positron emission tomography

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