Transition-metal-mediated bioconjugation chemistry has been used extensively to design and synthesize molecular probes to visualize, characterize, and quantify biological processes within intact living organisms at the cellular and subcellular levels. We demonstrate the development and validation of chemoselective [¹⁸F]fluoro-arylation chemistry of cysteine residues using Pd-mediated S-arylation chemistry with 4-[¹⁸F]fluoroiodobenzene ([¹⁸F]FIB) as an aryl electrophile. The novel bioconjugation technique proceeded in excellent radiochemical yields of 73–96% within 15 min under ambient and aqueous reaction mixture conditions, representing a versatile novel tool for decorating peptides and peptidomimetics with short-lived positron emitter ¹⁸F. The chemoselective S-arylation of several peptides and peptidomimetics containing multiple reactive functional groups confirmed the versatility and functional group compatibility. The synthesis and radiolabeling of a novel prostate-specific membrane antigen (PSMA) binding radioligand [¹⁸F]6 was accomplished using the novel labeling protocol. The validation of radioligand [¹⁸F]6 in a preclinical prostate cancer model with PET resulted in favorable accumulation and retention in PSMA-expressing LNCaP tumors. At the same time, a significantly lower salivary gland uptake was observed compared to clinical PSMA radioligand [¹⁸F]PSMA-1007. This finding coincides with ongoing discussions about the molecular basis of the off-target accumulation of PSMA radioligands currently used for clinical imaging and therapy of prostate cancer.

中文翻译：

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钯介导的 4-[18F]氟碘苯 ([18F]FIB) 对半胱氨酸残基进行 S 芳基化

过渡金属介导的生物共轭化学已被广泛用于设计和合成分子探针，以在细胞和亚细胞水平上可视化、表征和量化完整活有机体内的生物过程。我们展示了使用4-[ ¹⁸ F]氟碘苯（[ 18 F] ^{FIB ）作为芳基亲电子试剂的 Pd 介导的}S芳基化化学对半胱氨酸残基的化学选择性 [ ¹⁸ F]氟芳基化化学的开发和验证。在环境和水性反应混合物条件下，新型生物共轭技术在 15 分钟内取得了 73-96% 的优异放射化学产率，代表了一种用短寿命正电子发射体 18 ^F修饰肽和肽模拟物的多功能新工具。几种含有多个反应性官能团的肽和肽模拟物证实了其多功能性和官能团兼容性。使用新型标记方案完成了新型前列腺特异性膜抗原（PSMA）结合放射性配体[ ¹⁸ F]6的合成和放射性标记。在临床前前列腺癌模型中使用 PET验证放射性配体[ ¹⁸ F]6导致在表达 PSMA 的 LNCaP 肿瘤中产生有利的积累和保留。同时，与临床 PSMA 放射性配体 [ ¹⁸ F]PSMA-1007 相比，观察到唾液腺摄取显着降低。这一发现与目前用于前列腺癌临床成像和治疗的 PSMA 放射性配体脱靶积累的分子基础的讨论相吻合。