Dataset Information

Design, Synthesis, and Biological Evaluation of a Novel [¹⁸F]-Labeled Arginine Derivative for Tumor Imaging.

ABSTRACT: To better diagnose and treat tumors related to arginine metabolism, (2S,4S)-2-amino-4-(4-(2-(fluoro-¹⁸F)ethoxy)benzyl)-5-guanidinopentanoic acid ([¹⁸F]7) was designed and prepared by introducing [¹⁸F]fluoroethoxy benzyl on carbon-4 of arginine. [¹⁸F]7 and 7 were successfully prepared using synthesis methods similar to those used for (2S,4S)-4-[¹⁸F]FEBGln and (2S,4S)-4-FEBGln, respectively. In vitro experiments on cell transport mechanisms showed that [¹⁸F]7 was similar to (2S,4S)4-[¹⁸F]FPArg and was transported into tumor cells by cationic amino acid transporters. However, [¹⁸F]7 can also enter MCF-7 cells via ASC and ASC2 amino acid transporters. Further microPET-CT imaging showed that the initial uptake and retention properties of [¹⁸F]7 in MCF-7 subcutaneous tumors were good (2.29 ± 0.09%ID/g at 2.5 min and 1.71 ± 0.09%ID/g at 60 min after administration), without significant defluorination in vivo. However, compared to (2S,4S)4-[¹⁸F]FPArg (3.06 ± 0.59%ID/g at 60 min after administration), [¹⁸F]7 exhibited lower tumor uptake and higher nonspecific uptake. When further applied to U87MG imaging, [¹⁸F]7 can quickly visualize brain gliomas (tumor-to-brain, 1.85 at 60 min after administration). Therefore, based on the above results, [¹⁸F]7 will likely be applied for the diagnosis of arginine nutrition-deficient tumors and efficacy evaluations.

SUBMITTER: Huang Y

PROVIDER: S-EPMC10610273 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Biological Evaluation of a Novel [18F]-Labeled Arginine Derivative for Tumor Imaging.

Huang Yong Y Li Chengze C Li Zhongjing Z Xie Yi Y Chen Hualong H Li Shengli S Liang Ying Y Wu Zehui Z

Pharmaceuticals (Basel, Switzerland) 20231016 10

To better diagnose and treat tumors related to arginine metabolism, (2S,4S)-2-amino-4-(4-(2-(fluoro-18F)ethoxy)benzyl)-5-guanidinopentanoic acid ([18F]7) was designed and prepared by introducing [18F]fluoroethoxy benzyl on carbon-4 of arginine. [18F]7 and 7 were successfully prepared using synthesis methods similar to those used for (2S,4S)-4-[18F]FEBGln and (2S,4S)-4-FEBGln, respectively. In vitro experiments on cell tr ...[more]

PMID: 37895948

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Project description:BACKGROUND:Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. To address the continuously growing clinical demand for 18F-labeled PSMA-probes, we developed two novel Glu-urea-Glu-(EuE)-based inhibitors, EuE-k-18F-FBOA (1) and EuE-k-?-a-18F-FPyl (2), both with optimized linker structure and different 18F-labeled aromatic moieties. The inhibitors were evaluated in a comparative preclinical study with 18F-DCFPyl and 18F-PSMA-1007. RESULTS:Radiolabeling procedures allowed preparation of (1) and (2) with high radiochemical yields (67?±?7 and 53?±?7%, d.c.) and purity (>?98%). When compared with 18F-DCFPyl (IC50 = 12.3?±?1.2 nM) and 18F-PSMA-1007 (IC50 = 4.2?±?0.5 nM), both metabolically stable EuE-based ligands showed commensurable or higher PSMA affinity (IC50 = 4.2?±?0.4 nM (1), IC50 = 1.1?±?0.2 nM (2)). Moreover, 1.4- and 2.7-fold higher internalization rates were observed for (1) and (2), respectively, resulting in markedly enhanced tumor accumulation in LNCaP-tumor-bearing mice ((1) 12.7?±?2.0% IA/g, (2) 13.0°?±?1.0% IA/g vs. 7.3?±?1.0% IA/g (18F-DCFPyl), 7.1?±?1.5% IA/g (18F-PSMA-1007), 1 h p.i.). In contrast to (1), (2) showed higher kidney accumulation and delayed clearance kinetics. Due to the high hydrophilicity of both compounds, almost no unspecific uptake in non-target tissue was observed. In contrast, due to the less hydrophilic character (logP?=?-?1.6) and high plasma protein binding (98%), 18F-PSMA-1007 showed uptake in non-target tissue and predominantly hepatobiliary excretion, whereas, 18F-DCFPyl exhibited pharmacokinetics quite similar to those obtained with (1) and (2). CONCLUSION:Both 18F-labeled EuE-based PSMA ligands showed excellent in vitro and in vivo PSMA-targeting characteristics. The substantially higher tumor accumulation in mice compared to recently introduced 18F-PSMA-1007 and 18F-DCFPyl suggests their high value for preclinical studies investigating the effects on PSMA-expression. In contrast to (2), (1) seems to be more promising for further investigation, due to the more reliable 18F-labeling procedure, the faster clearance kinetics with comparable high tumor uptake, resulting therefore in better high-contrast microPET imaging as early as 1 h p.i.

Dataset Information

Design, Synthesis, and Biological Evaluation of a Novel [¹⁸F]-Labeled Arginine Derivative for Tumor Imaging.

Publications

Design, Synthesis, and Biological Evaluation of a Novel [<sup>18</sup>F]-Labeled Arginine Derivative for Tumor Imaging.

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