Development of a 18F‑Labeled Bicyclic Peptide Targeting EphA2 for Molecular Imaging of PSMA-Negative Prostate Cancer

Although PSMA PET/CT imaging has great potential for
noninvasively
detecting prostate cancer (PCa), limitations exist for patients with
low PSMA expression, caused by androgen deprivation treatment or neuroendocrine
differentiation. Analysis of The Cancer Genome Atlas Prostate Adenocarcinoma
(TCGA-PRAD) data found that erythropoietin-producing hepatocellular
receptor A2 (EphA2), a receptor overexpressed in most PCa could be
a potential target for PSMA-negative PCa. A fluorescent ligand ETF
and a radiolabeled ligand [18F]AlF-ETN derived from a EphA2-targeting
bicyclic peptide were synthesized and investigated. ETF could selectively
stain and visualize the EphA2-positive but PSMA-negative PC3 cells,
in complementary to the PSMA-targeting probe. PET/CT imaging and biodistribution
experiments demonstrated that [18F]AlF-ETN specifically
accumulated in PC3 tumors with a high contrast (tumor-to-muscle ratio:
21.29 ± 6.55). In conclusion, we have demonstrated the potential
for using EphA2 to detect PSMA-negative PCa and developed a radiolabeled
ligand [18F]AlF-ETN to specifically image EphA2 expressing
PCa with high contrast.

尽管PSMA PET/CT成像技术在非侵入性检测前列腺癌（PCa）方面具有巨大的潜力，但对于接受雄激素剥夺治疗或神经内分泌分化的患者，由于PSMA表达量低，仍存在一定的局限性。通过对癌症基因组图谱前列腺腺癌（TCGA-PRAD）数据的分析，发现红细胞生成素产生性肝细胞受体A2（EphA2），一种在大多数前列腺癌中过表达的受体，可能成为PSMA阴性PCa的潜在靶点。合成了针对EphA2的环状肽荧光配体ETF和放射性标记配体[18F]AlF-ETN，并对其进行了研究。ETF能够选择性地染色和可视化EphA2阳性但PSMA阴性的PC3细胞，与PSMA靶向探针互补。PET/CT成像和生物分布实验表明，[18F]AlF-ETN能够特异性地积累在PC3肿瘤中，具有高对比度（肿瘤与肌肉比：21.29 ± 6.55）。综上所述，本研究证实了利用EphA2检测PSMA阴性PCa的潜力，并开发了一种放射性标记配体[18F]AlF-ETN，以高对比度特异性成像表达EphA2的前列腺癌。