18F-Fluorobenzoate–Labeled Cystine Knot Peptides for PET Imaging of Integrin αvβ6

Journal of Nuclear Medicine

Frederick T. Chin¹  Hongguang Liu¹  Benjamin J. Hackel¹  Zheng Miao¹  Ataya Sathirachinda¹  Sanjiv S. Gambhir¹  Richard H. Kimura¹  Zhen Cheng¹ 

关键词: integrin α_vβ₆;    positron emission tomography;    cystine knot;   

DOI  :  10.2967/jnumed.112.110759

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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-4-18F-fluorobenzoate 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 γ-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 18F-fluorobenzoate-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 18F-fluorobenzoate-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 = 4–5). Target specificity was confirmed by low tumor uptake in integrin αvβ6–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 = 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 γ-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 18F-fluorobenzoate-S02; n = 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 = 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.

【 授权许可】

Unknown