Ramogida Caterina F, Pan Jinhe, Ferreira Cara L, Patrick Brian O, Rebullar Karla, Yapp Donald T T, Lin Kuo-Shyan, Adam Michael J, Orvig Chris
†Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
‡TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Inorg Chem. 2015 May 18;54(10):4953-65. doi: 10.1021/acs.inorgchem.5b00554. Epub 2015 Apr 30.
(68)Ga is an attractive radiometal for use in positron emission tomography (PET) imaging. The success of (68)Ga-based agents is dependent on a chelator that exhibits rapid radiometal incorporation, and strong kinetic inertness to prevent transchelation of (68)Ga in vivo. The linear chelating agents H2dedpa (1,2-[[6-carboxypyridin-2-yl]methylamino]ethane) and H2CHXdedpa (CHX = cyclohexyl/cyclohexane) (N4O2) have recently been developed that bind Ga(3+) quickly and under mild conditions, ideal properties to be incorporated into a (68)Ga PET imaging agent. Herein, nitroimidazole (NI) derivatives of H2dedpa and H2CHXdedpa to investigate specific targeting of hypoxic tumor cells are investigated, given that NI can be reduced and retained exclusively in hypoxic cells. Nine N,N'-bis-alkylated derivatives of H2dedpa and H2CHXdedpa have been synthesized; they have been screened for their ability to bind gallium, and cyclic voltammetry of nonradioactive complexes was performed to probe the redox cycling mechanism of NI. The compounds were radiolabeled with (67)Ga and (68)Ga and show promising radiolabeling efficiencies (>99%) when labeled at 10(-5) M for 10 min at room temperature. Moreover, stability studies (via apo-transferrin challenge, 37 °C) show that the (67)Ga complexes exhibit exceptional stability (86-99% intact) after 2 h. In vitro uptake studies under hypoxic (0.5% O2) and normoxic (21% O2) conditions in three cancerous cell lines [HT-29 (colon), LCC6(HER-2) (breast), and CHO (Chinese hamster ovarian)] were performed. Of the four H2dedpa or H2CHXdedpa NI derivatives tested, all showed preferential uptake in hypoxic cells compared to normoxic cells with hypoxic/normoxic ratios as high as 7.9 ± 2.7 after 120 min. The results suggest that these novel bis-alkylated NI-containing H2dedpa and H2CHXdedpa ligands would be ideal candidates for further testing in vivo for PET imaging of hypoxia with (68)Ga.
镓-68是一种用于正电子发射断层扫描（PET）成像的有吸引力的放射性金属。基于镓-68的试剂的成功取决于一种螯合剂，该螯合剂能快速结合放射性金属，并具有很强的动力学惰性，以防止镓-68在体内发生转螯合。线性螯合剂H2dedpa（1,2-[[6-羧基吡啶-2-基]甲基氨基]乙烷）和H2CHXdedpa（CHX = 环己基/环己烷）（N4O2）最近已被开发出来，它们能在温和条件下快速结合Ga(3+)，这是被纳入镓-68 PET成像剂的理想特性。鉴于硝基咪唑（NI）可被还原并仅保留在缺氧细胞中，本文研究了H2dedpa和H2CHXdedpa的硝基咪唑衍生物，以研究缺氧肿瘤细胞的特异性靶向。已合成了九种H2dedpa和H2CHXdedpa的N,N'-双烷基化衍生物；对它们结合镓的能力进行了筛选，并对非放射性配合物进行了循环伏安法研究，以探究NI的氧化还原循环机制。这些化合物用镓-67和镓-68进行了放射性标记，在室温下以10(-5) M标记10分钟时，显示出有前景的放射性标记效率（>99%）。此外，稳定性研究（通过脱铁转铁蛋白挑战，37°C）表明，镓-67配合物在2小时后表现出卓越的稳定性（86-99%完整）。在三种癌细胞系[HT-29（结肠）、LCC6(HER-2)（乳腺）和CHO（中国仓鼠卵巢）]的缺氧（0.5% O2）和常氧（21% O2）条件下进行了体外摄取研究。在所测试的四种H2dedpa或H2CHXdedpa NI衍生物中，与常氧细胞相比，所有衍生物在缺氧细胞中均表现出优先摄取，120分钟后缺氧/常氧比高达7.9±2.7。结果表明，这些新型含双烷基化NI的H2dedpa和H2CHXdedpa配体将是用镓-68进行缺氧PET成像体内进一步测试的理想候选物。
