서강대, KIRAMS / 이병세, 지대윤*, 이교철*
Abstract
Background: Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library.
Method: 18 F-labeling was achieved in a two-step synthesis consisting of [18 F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA- PC3-flu cells and 22RV1 cells. [125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [18 F]DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software.
Results: Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (Ki ). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [18 F]6c had the lowest log P of -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [18 F]6c, [18 F]6f, and [18 F]6i. Additional microPET/CT experiments of [18 F]6c and [18 F]6f were performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [18 F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10-3 mSv/MBq.
Conclusions: [18 F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.
Affiliations
Byoung Se Lee 1 , So Young Chu 1 , Woon Jung Jung 1 , Hyeon Jin Jeong 1 , Kyongkyu Lee 1 , Min Hwan Kim 1 , Mi Hyun Kim 1 , Dae Yoon Chi 1 2 , Heesu Ahn 3 , Yong Jin Lee 3 , Kyo Chul Lee 3 , Sang Moo Lim 4
1 Research Institute of Labeling, FutureChem Co., Ltd., Seoul, Republic of Korea.
2 Department of Chemistry, Sogang University, Seoul, Republic of Korea.
3 Division of Applied RI, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
4 Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
편집위원
전립선암을 특이적 영상에 가능한 새로운 방사성의약품을 개발하고 이의 전립선암의 특이적 섭취와 dosimetric 결과를 확인한 전임상 연구임. Theranostic agent로 이용이 가능할 수 있으며, 전립선암 및 핵의학 임상가 및 방사화학자에게 관심을 유도할 연구로 생각됨.
2021-01-26 15:16:59