环己二胺三唑（CHDT）功能化可以用Al18f/68ga/111in标记目标分子
Cyclohexanediamine Triazole (CHDT) Functionalization Enables Labeling of Target Molecules with Al18F/68Ga/111In
影响因子:3.90000
分区:化学2区 / 生化研究方法2区 有机化学2区 生化与分子生物学3区 化学：综合3区
发表日期:2024 Sep 18
作者:
Wiebke Sihver, Martin Walther, Martin Ullrich, Anne-Kathrin Nitt-Weber, Jenny Böhme, Falco Reissig, Magdalena Saager, Kristof Zarschler, Christin Neuber, Jörg Steinbach, Klaus Kopka, Hans-Jürgen Pietzsch, Robert Wodtke, Jens Pietzsch
摘要
AL18F标签方法通过模仿放射线仪的标签过程，提供了对射线荧光的生物分子的一步访问。尽管与经典的放射性荧光相比，这些标记条件被认为是温和的，但螯合单元的改进导致发现（±）-H3Resca，这使得AL18F标记已经在环境温度下。虽然（±）-H3Resca对蛋白质的功能化和放射性荧光的适用性已得到很好的确定，但探索了其用于小分子或肽的使用。本文中，我们通过引入一个通过点击化学引入生物分子的晚期功能化来提出这种无环五齿配体。我们表明，除了AL18F标记外，环己胺三唑（CHDT）部分还允许稳定的68GA和111in络合。合成了三种新型的CHDT官能化的PSMA抑制剂，并将其AL18F-，68GA-和111in标记的类似物进行详细的体外放射性药物表征。在人血清中体外的稳定性研究表明，所有辐射仪复合物具有很高的动力学惰性。此外，通过PET成像，AL18F标记的PSMA配体在LNCAP衍生的肿瘤异种移植小鼠模型中以其生物分布为特征。一个放射性物体，Al [18F] F-CHDT-PSMA-1，在谷氨酸酸酯 - 氨基赖氨酸 - 赖氨酸基序中带有一个小叠氮乙酰基接头，提供了与[18F] PSMA-1007相当的体内性能，但甚至具有较高的肿瘤至肿瘤 - 肿瘤至肿瘤 - 肿瘤与肿瘤比率，在120分钟P.i的P.i。总体而言，我们的结果突出了新型CHDT部分对具有AL18F，68GA和111IN的小分子或肽的功能化和放射性标记的适用性，而三唑环似乎需要有利的药代性质用于分子成像的目的。
Abstract
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.