Marlin Axia, Tran Phuong Nguyen, Dierolf Morgan, DeLuca Molly, Joaqui Joaqui M Andrey, Glaser Owen M, Koller Angus J, Alucio-Sarduy Eduardo, Gork Mallory, Śmiłowicz Dariusz, Pierre Valérie, Engle Jonathan W, Boros Eszter
Department of Chemistry, University of Wisconsin Madison, 1101 University Avenue, Madison, Wisconsin 53705, United States.
Department of Medical Physics, University of Wisconsin Madison, 1111 Highland Avenue, Madison, Wisconsin 53705, United States.
Bioconjug Chem. 2025 Apr 16;36(4):859-866. doi: 10.1021/acs.bioconjchem.5c00099. Epub 2025 Mar 18.
Chelation approaches that are compatible with a multitude of isotopes are an important area of development. Here, we introduce the design, synthesis, and evaluation of 2,3-dihydroxyterephthalate/catechol chelator conjugates compatible with the positron emission tomography (PET) isotopes Ga and Ti, targeting the prostate-specific membrane antigen (PSMA). The conjugates are made in a multistep organic synthesis incorporating 2,3-dihydroxyterephthalate, linked to the amino hexanoic acid-extended, urea-dipeptides EuE or KuE (substrates of the PSMA active site). The radiochemical complexes, [Ti][Ti(TREN-CAM-hex-EuE)], [Ti][Ti(TREN-CAM-hex-KuE)], and [Ga][Ga(TREN-CAM-hex-KuE)] form readily at room temperature within 15 min with a molar activity of 24-29 mCi/μmol. The corresponding chelates are stable in phosphate-buffered saline (PBS) solution prior to injection. Subsequent in vivo studies in a bilateral tumor xenograft mouse model were conducted, including 90- and 270-min PET, followed by biodistribution and metabolite analysis at 2 or 5 h postinjection. These studies demonstrated selective uptake of the radiochemical complexes in the PSMA-expressing tumor (17.25 ± 4.15, 13.84 ± 3.85, 15.64 ± 6.37% ID/g for [Ti][Ti(TREN-CAM-hex-EuE)], [Ti][Ti(TREN-CAM-hex-KuE)] and [Ga][Ga(TREN-CAM-hex-KuE)] respectively), with pharmacokinetics dominated by renal clearance. Delayed clearance of the [Ti][Ti(TREN-CAM-hex-KuE)] complex is observed when compared with that of [Ga][Ga(TREN-CAM-hex-KuE)] as indicated by elevated activity retention in the blood, which we attribute to the charge difference and partial complex dissociation. Urine metabolite analysis shows that [Ga][Ga(TREN-CAM-hex-KuE)] is excreted >98% intact, while [Ti][Ti(TREN-CAM-hex-KuE)] exhibited signs of dechelation. Conclusively, our data support further investigation of bifunctional TREN-CAM derivatives as a synthetically accessible bifunctional chelator class for Ga and Ti isotopes.
与多种同位素兼容的螯合方法是一个重要的发展领域。在此，我们介绍了与正电子发射断层扫描（PET）同位素镓和钛兼容的2,3-二羟基对苯二甲酸/儿茶酚螯合剂共轭物的设计、合成和评估，其靶向前列腺特异性膜抗原（PSMA）。这些共轭物通过多步有机合成制备，其中包含与氨基己酸延伸的脲二肽EuE或KuE（PSMA活性位点的底物）相连的2,3-二羟基对苯二甲酸。放射性化学配合物[Ti][Ti(TREN-CAM-hex-EuE)]、[Ti][Ti(TREN-CAM-hex-KuE)]和[Ga][Ga(TREN-CAM-hex-KuE)]在室温下15分钟内即可轻松形成，摩尔活度为24-29 mCi/μmol。相应的螯合物在注射前的磷酸盐缓冲盐水（PBS）溶液中稳定。随后在双侧肿瘤异种移植小鼠模型中进行了体内研究，包括90分钟和270分钟的PET扫描，随后在注射后2或5小时进行生物分布和代谢物分析。这些研究表明，放射性化学配合物在表达PSMA的肿瘤中具有选择性摄取（[Ti][Ti(TREN-CAM-hex-EuE)]、[Ti][Ti(TREN-CAM-hex-KuE)]和[Ga][Ga(TREN-CAM-hex-KuE)]分别为17.25±4.15、13.84±3.85、15.64±6.37% ID/g），其药代动力学以肾脏清除为主。与[Ga][Ga(TREN-CAM-hex-KuE)]相比，观察到[Ti][Ti(TREN-CAM-hex-KuE)]配合物的清除延迟，这表现为血液中活性保留升高，我们将其归因于电荷差异和部分配合物解离。尿液代谢物分析表明，[Ga][Ga(TREN-CAM-hex-KuE)]以>98%的完整形式排泄，而[Ti][Ti(TREN-CAM-hex-KuE)]表现出脱螯合的迹象。总之，我们的数据支持进一步研究双功能TREN-CAM衍生物，作为一种可通过合成获得的用于镓和钛同位素的双功能螯合剂类别。
