Al18F 标记方法通过模仿放射性金属的标记过程，提供了一种一步获得放射性氟化生物分子的方法。尽管与经典的放射性氟化相比，这些标记条件被认为是温和的，但螯合单元的改进导致了 (±)-H3RESCA 的发现，它允许在环境温度下进行 Al18F 标记。虽然 (±)-H3RESCA 对于蛋白质功能化和放射性氟化的适用性已得到充分证实，但其在小分子或肽中的应用却很少被探索。在这里，我们通过引入炔部分来通过点击化学对生物分子进行后期功能化来改进这种无环五齿配体。我们表明，除了 Al18F 标记之外，环己烷二胺三唑 (CHDT) 部分还可以稳定 68Ga 和 111In 络合。合成了三种新型 CHDT 功能化 PSMA 抑制剂，并对它们的 Al18F、68Ga 和 111In 标记类似物进行了详细的体外放射药理学表征。人血清体外稳定性研究表明，所有放射性金属配合物均具有高动力学惰性。此外，通过 PET 成像，对 Al18F 标记的 PSMA 配体在 LNCaP 衍生的肿瘤异种移植小鼠模型中的生物分布进行了表征。一种放射性配体 Al[18F]F-CHDT-PSMA-1 在谷氨酸-尿素-赖氨酸基序上带有一个小的叠氮乙酰接头，其体内性能与 [18F]PSMA-1007 相当，但具有更高的肿瘤抑制作用。注射后 120 分钟时的血液与肿瘤与肌肉比率总体而言，我们的结果强调了新型 CHDT 部分适用于用 Al18F、68Ga 和 111In 对小分子或肽进行功能化和放射性标记，并且三唑环似乎具有用于分子成像目的的有利药代动力学特性。

The Al18F-labeling approach offers a one-step access to radiofluorinated biomolecules by mimicking the labeling process for radiometals. Although these labeling conditions are considered to be mild compared to classic radiofluorinations, improvements of the chelating units have led to the discovery of (±)-H3RESCA, which allows Al18F-labeling already at ambient temperature. While the suitability of (±)-H3RESCA for functionalization and radiofluorination of proteins is well established, its use for small molecules or peptides is less explored. Herein, we advanced this acyclic pentadentate ligand by introducing an alkyne moiety for the late-stage functionalization of biomolecules via click chemistry. We show that in addition to Al18F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of 68Ga and 111In. Three novel CHDT-functionalized PSMA inhibitors were synthesized and their Al18F-, 68Ga-, and 111In-labeled analogs were subjected to a detailed in vitro radiopharmacological characterization. Stability studies in vitro in human serum revealed among others a high kinetic inertness of all radiometal complexes. Furthermore, the Al18F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, Al[18F]F-CHDT-PSMA-1, bearing a small azidoacetyl linker at the glutamate-urea-lysine motif, provided an in vivo performance comparable to that of [18F]PSMA-1007 but with even higher tumor-to-blood and tumor-to-muscle ratios at 120 min p.i. Overall, our results highlight the suitability of the novel CHDT moiety for functionalization and radiolabeling of small molecules or peptides with Al18F, 68Ga, and 111In and the triazole ring seems to entail favorable pharmacokinetic properties for molecular imaging purposes.