Wang Lei, Kuo Hsiou-Ting, Chapple Devon E, Chen Chao-Cheng, Kurkowska Sara, Colpo Nadine, Uribe Carlos, Bénard François, Lin Kuo-Shyan
Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, British Columbia V5Z 1L3, Canada.
Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, British Columbia V5Z 1L3, Canada.
Mol Pharm. 2024 Dec 2;21(12):6385-6397. doi: 10.1021/acs.molpharmaceut.4c00952. Epub 2024 Oct 26.
The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of cancers and represents a promising target for diagnosis and therapy. However, the extremely high accumulation in the pancreas observed for most of the clinically evaluated GRPR-targeted radiopharmaceuticals could limit their applications. In this study, we synthesized one GRPR antagonist (ProBOMB5) and two GRPR agonists (LW02056 and LW02057) by replacing the 4-thiazolidinecarboxylic acid (Thz) residue in our previously reported GRPR-targeted tracers with Pro. The Ga and Lu labeling were conducted in HEPES (2 M, pH 5.0) buffer and acetate (0.1 M, pH 4.5) buffer, respectively, and the radiolabeled products were obtained in a 24-57% decay-corrected radiochemical yield and >92% radiochemical purity. The binding affinities () of Ga-ProBOMB5, Ga-LW02056, Ga-LW02057, and Lu-ProBOMB5 were measured via competition binding assays and were 12.2 ± 1.89, 14.7 ± 4.81, 13.8 ± 2.24, and 13.6 ± 0.25 nM, respectively. The PET imaging and biodistribution studies were conducted in PC-3 tumor-bearing mice at 1 h post injection. [Ga]Ga-ProBOMB5, [Ga]Ga-LW02056, and [Ga]Ga-LW02057 enabled clear tumor visualization in PET images. The tumor uptake values of [Ga]Ga-ProBOMB5, [Ga]Ga-LW02056, and [Ga]Ga-LW02057 were 12.4 ± 1.35, 8.93 ± 1.96, and 7.64 ± 0.55%ID/g, respectively, and their average pancreas uptake values were minimal (0.60-1.37%ID/g). Longitudinal SPECT imaging and biodistribution studies were also conducted for [Lu]Lu-ProBOMB5 and clinically validated [Lu]Lu-RM2. Despite comparable tumor uptake at 1 h post injection ([Lu]Lu-ProBOMB5:8.09 ± 1.70%ID/g; [Lu]Lu-RM2:7.73 ± 0.96%ID/g), a faster clearance from PC-3 tumor xenografts was observed for [Lu]Lu-ProBOMB5, leading to a lower radiation-absorbed dose delivered to tumors. Our data demonstrate that [Ga]Ga-ProBOMB5 is a promising tracer for clinical translation for detecting GRPR-expressing tumor lesions. However, further optimizations are needed for [Lu]Lu-ProBOMB5 to prolong tumor retention for therapeutic applications.
胃泌素释放肽受体（GRPR）在多种癌症中过表达，是诊断和治疗的一个有前景的靶点。然而，大多数临床评估的GRPR靶向放射性药物在胰腺中观察到的极高蓄积可能会限制它们的应用。在本研究中，我们通过用脯氨酸（Pro）取代我们之前报道的GRPR靶向示踪剂中的4-噻唑烷羧酸（Thz）残基，合成了一种GRPR拮抗剂（ProBOMB5）和两种GRPR激动剂（LW02056和LW02057）。镓和镥标记分别在HEPES（2 M，pH 5.0）缓冲液和醋酸盐（0.1 M，pH 4.5）缓冲液中进行，放射性标记产物的衰变校正放射化学产率为24 - 57%，放射化学纯度>92%。通过竞争结合试验测量了镓 - ProBOMB5、镓 - LW02056、镓 - LW02057和镥 - ProBOMB5的结合亲和力（），分别为12.2±1.89、14.7±4.81、13.8±2.24和13.6±0.25 nM。在注射后1小时对荷PC - 3肿瘤的小鼠进行PET成像和生物分布研究。[镓]镓 - ProBOMB5、[镓]镓 - LW02056和[镓]镓 - LW02057在PET图像中能够清晰地显示肿瘤。[镓]镓 - ProBOMB5、[镓]镓 - LW02056和[镓]镓 - LW02057的肿瘤摄取值分别为12.4±1.35、8.93±1.96和7.64±0.55%ID/g，它们的平均胰腺摄取值最小（0.60 - 1.37%ID/g）。还对[镥]镥 - ProBOMB5和经临床验证的[镥]镥 - RM2进行了纵向SPECT成像和生物分布研究。尽管在注射后1小时肿瘤摄取相当（[镥]镥 - ProBOMB5：8.09±1.70%ID/g；[镥]镥 - RM2：
