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Abstract
Background: 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 64Cu-chelating agents in newly developed prostate-specific membrane antigen (PSMA) target compounds, 64Cu-cudotadipep and 64Cu-cunotadipep, on pharmacokinetics.

Methods: 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.

Results: The serum stability of DOTA- or NOTA-conjugated 64Cu-cudotadipep and 64Cu-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 × 106 cells) compared with the cudotadipep (2.93 ± 0.06%/1 × 106 cells). In the biodistribution analysis and microPET/CT imaging, the 64Cu-labeled NOTA derivative, 64Cu-cunotadipep, demonstrated a greater tumor uptake and lower liver uptake than the DOTA derivative.

Conclusions: This study indicates that the PSMA-targeted 64Cu-cunotadipep can be applied in clinical practice owing to its high diagnostic power for prostate cancer.

Affiliations

Inki Lee 1, Min Hwan Kim 2, Kyongkyu Lee 2, Keumrok Oh 2, Hyunwoo Lim 2, Jae Hun Ahn 3 4, Yong Jin Lee 3, Gi Jeong Cheon 5, Dae Yoon Chi 2, Sang Moo Lim 1
1Department of Nuclear Medicine, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
2Research Institute of Radiopharmaceuticals, FutureChem Co., Ltd., Seoul 04793, Republic of Korea.
3Division of Applied RI, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
4Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
5Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.