PURPOSE The αvβ6-BP peptide selectively targets the integrin αvβ6, a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[18F]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [18F]fluoride chelation and introduction of an albumin binding moiety (ABM) have the potential to considerably simplify radiochemistry and improve the pharmacokinetics by increasing biological half-life. PROCEDURES The peptides NOTA-αvβ6-BP (1) and NOTA-K(ABM)-αvβ6-BP (2) were synthesized on solid phase, radiolabeled with aluminum [18F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puroβ6 [αvβ6(+)]/DX3puro [αvβ6(-)], and for [18F]AlF 2, BxPC-3 [αvβ6(+)] cell xenografts (PET imaging, biodistribution). RESULTS The peptides were radiolabeled in 23.0 ± 5.7 % and 22.1 ± 4.4 % decay-corrected radiochemical yield, respectively, for [18F]AlF 1 and [18F]AlF 2. Both demonstrated excellent affinity and selectivity for integrin αvβ6 by ELISA (IC50(αvβ6) = 3-7 nM vs IC50(αvβ3) > 10 μM) and in cell binding studies (51.0 ± 0.7 % and 47.2 ± 0.7 % of total radioactivity bound to DX3puroβ6 cells at 1 h, respectively, vs. ≤ 1.2 % to DX3puro for both compounds). The radiotracer [18F]AlF 1 bound to human serum at 16.3 ± 1.9 %, compared to 67.5 ± 1.0 % for the ABM-containing [18F]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (≤ 0.1 % ID/g remaining in blood for [18F]AlF 1 as soon as 1 h p.i. vs. > 2 % ID/g for [18F]AlF 2 at 6 h p.i.) and higher αvβ6(+) tumor uptake (4 h: DX3puroβ6; [18F]AlF 1: 3.0 ± 0.7 % ID/g, [18F]AlF 2: 7.2 ± 0.7 % ID/g; BxPC-3; [18F]AlF 2: 10.2 ± 0.1 % ID/g). CONCLUSION Both compounds were prepared using standard chemistries; affinity and selectivity for integrin αvβ6 in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher αvβ6-targeted uptake.

中文翻译：

---

白蛋白结合部分对用铝 [18F] 氟化物标记的整合素 αvβ6-选择性肽的靶向和药代动力学的影响。

目的 αvβ6-BP 肽选择性地靶向整合素 αvβ6，这是一种细胞表面受体，被认为是几种具有挑战性的恶性肿瘤的预后指标。鉴于 4-[18F] 氟苯甲酰基 (FBA) 标记的肽是一种有前途的 PET 显像剂，通过铝 [18F] 氟化物螯合和引入白蛋白结合部分 (ABM) 进行放射性标记有可能大大简化放射化学并改善通过增加生物半衰期的药代动力学。程序 在固相上合成肽 NOTA-αvβ6-BP (1) 和 NOTA-K(ABM)-αvβ6-BP (2)，用铝 [18F] 氟化物进行放射性标记，并在体外进行评估（整合素 ELISA、白蛋白结合、细胞研究）和体内带有配对 DX3puroβ6 [αvβ6(+)]/DX3puro [αvβ6(-)] 和 [18F]AlF 2、BxPC-3 [αvβ6(+)] 细胞异种移植物的小鼠模型（PET 成像，生物分布）。结果 对于 [18F]AlF 1 和 [18F]AlF 2，肽分别以 23.0 ± 5.7 % 和 22.1 ± 4.4 % 的衰变校正放射化学产率进行放射性标记。通过 ELISA（IC50（IC50（ αvβ6) = 3-7 nM 与 IC50(αvβ3) > 10 μM) 和细胞结合研究（1 小时时与 DX3puroβ6 细胞结合的总放射性分别为 51.0 ± 0.7 % 和 47.2 ± 0.7 %，对比 ≤ 1.2 % DX3puro 用于两种化合物）。放射性示踪剂 [18F]AlF 1 与人血清的结合率为 16.3 ± 1.9 %，而含有 ABM 的 [18F]AlF 2 为 67.5 ± 1.0 %。体内研究证实了 ABM 对血液循环的影响（≤ 0.1 % [18F]AlF 1 注射后 1 小时后血液中剩余的 ID/g 与 [18F]AlF 2 在注射后 6 小时时 > 2 % ID/g) 和更高的 αvβ6(+) 肿瘤摄取（4 小时：DX3puroβ6 ; [18F]AlF 1: 3.0 ± 0.7 % ID/g, [18F]AlF 2：7.2 ± 0.7 % ID/g；BxPC-3；[18F]AlF 2：10.2 ± 0.1 % ID/g)。结论 两种化合物均使用标准化学方法制备；体外对整合素αvβ6的亲和力和选择性不受白蛋白结合部分的影响。在体内，白蛋白结合部分导致循环延长和更高的 αvβ6 靶向摄取。