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Abstract
We developed a novel therapeutic radioligand, [177Lu]1h, with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an in vitro competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([68Ga]1e, [68Ga]1g, [68Ga]1h, and [68Ga]1k) were screened for tumor targeting efficiency by micro-positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [177Lu]1h compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro-single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound 1h showed a high binding affinity (Ki value = 4.08 ± 0.08 nmol/L), and [177Lu]1h showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [177Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [177Lu]1h was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [177Lu]1h showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [177Lu]1h survived for the entire monitoring period. The estimated human effective dose of [177Lu]1h was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [177Lu]1h has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials.

Ludotadipep의 구조

그림 1. Micro SPECT/CT 영상과 ROI 값. 전립선암을 가지고 있는 마우스에 [177Lu]Ludotadipep 주사 후 2, 6, 24, 48, 72 시간에서의 micro SPECT/CT 영상 (A), 그리고 ROI 평균 값 (B) (n = 4/그룹).

그림 2. PC3-PIP 전립선암을 가지고 있는 마우스에 대한 [177Lu]Ludotadipep의 치료 효과. [177Lu]Ludotadipep를 2, 4, 6 MBq 단일 투여한 경우와 처리하지 않은 마우스에 대한 암 부피의 변화 (A)와 survival rate (B).

Affiliations

Byoung Se Lee  1 , Min Hwan Kim  1 , So Young Chu  1 , Woon Jung Jung  1 , Hyeon Jin Jeong  1 , Kyongkyu Lee  1 , Hyeon Seok Kim  1 , Mi Hyun Kim  1 , Hee Seup Kil  1 , Sang Jin Han  2 , Yong Jin Lee  2 , Kyo Chul Lee  2 , Sang Moo Lim  3 , Dae Yoon Chi  4
1 Research Institute of Labeling, FutureChem Co., Ltd., Seoul, Republic of Korea.
2 Division of Applied RI, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
3 Department of Nuclear Medicine, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
4 Research Institute of Labeling, FutureChem Co., Ltd., Seoul, Republic of Korea. dychi001@gmail.com.