Lee Inki, Kim Min Hwan, Lee Kyongkyu, Oh Keumrok, Lim Hyunwoo, Ahn Jae Hun, Lee Yong Jin, Cheon Gi Jeong, Chi Dae Yoon, Lim Sang Moo
Department of Nuclear Medicine, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
Research Institute of Radiopharmaceuticals, FutureChem Co., Ltd., Seoul 04793, Republic of Korea.
Diagnostics (Basel). 2023 Aug 11;13(16):2649. doi: 10.3390/diagnostics13162649.
This study compared the effects of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) as Cu-chelating agents in newly developed prostate-specific membrane antigen (PSMA) target compounds, Cu-cudotadipep and Cu-cunotadipep, on pharmacokinetics.
The in vitro stability of the chelators was evaluated using human and mouse serum. In vitro PSMA-binding affinity and cell uptake were compared using human 22Rv1 cells. To evaluate specific PSMA-expressing tumor-targeting efficiency, micro-positron emission tomography (mcroPET)/computed tomography (CT) and biodistribution analysis were performed using PSMA+ PC3-PIP and PSMA- PC3-flu tumor xenografts.
The serum stability of DOTA- or NOTA-conjugated Cu-cudotadipep and Cu-cunotadipep was >97%. The Ki value of the NOTA derivative, cunotadipep, in the in vitro affinity binding analysis was higher (2.17 ± 0.25 nM) than that of the DOTA derivative, cudotadipep (6.75 ± 0.42 nM). The cunotadipep exhibited a higher cellular uptake (6.02 ± 0.05%/1 × 10 cells) compared with the cudotadipep (2.93 ± 0.06%/1 × 10 cells). In the biodistribution analysis and microPET/CT imaging, the Cu-labeled NOTA derivative, Cu-cunotadipep, demonstrated a greater tumor uptake and lower liver uptake than the DOTA derivative.
This study indicates that the PSMA-targeted Cu-cunotadipep can be applied in clinical practice owing to its high diagnostic power for prostate cancer.
本研究比较了1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）和1,4,7-三氮杂环壬烷-1,4,7-三乙酸（NOTA）作为铜螯合剂在新开发的前列腺特异性膜抗原（PSMA）靶向化合物铜-双肽和铜-诺他双肽中的药代动力学影响。
使用人和小鼠血清评估螯合剂的体外稳定性。使用人22Rv1细胞比较体外PSMA结合亲和力和细胞摄取。为了评估特异性表达PSMA的肿瘤靶向效率，使用PSMA+ PC3-PIP和PSMA- PC3-flu肿瘤异种移植进行微正电子发射断层扫描（mcroPET）/计算机断层扫描（CT）和生物分布分析。
DOTA或NOTA共轭的铜-双肽和铜-诺他双肽的血清稳定性>97%。在体外亲和力结合分析中，NOTA衍生物诺他双肽的Ki值（2.17±0.25 nM）高于DOTA衍生物双肽（6.75±0.42 nM）。与双肽（2.93±0.06%/1×10细胞）相比，诺他双肽表现出更高的细胞摄取（6.02±0.05%/1×10细胞）。在生物分布分析和微PET/CT成像中，铜标记的NOTA衍生物铜-诺他双肽比DOTA衍生物表现出更高的肿瘤摄取和更低的肝脏摄取。
本研究表明，PSMA靶向的铜-诺他双肽因其对前列腺癌的高诊断能力可应用于临床实践。
