PDF(Pubmed)
Abstract：
Gastrin-releasing peptide receptor (GRPR), overexpressed in many solid tumors, is a promising imaging marker and therapeutic target. Most reported GRPR-targeted radioligands contain a C-terminal amide. Based on the reported potent antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH, we synthesized C-terminal hydroxamate-derived [68Ga]Ga-LW02075 ([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH) and [68Ga]Ga-LW02050 ([68Ga]Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH), and compared them with the closely related and clinically validated [68Ga]Ga-SB3 ([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt). Binding affinities (Ki) of Ga-SB3, Ga-LW02075, and Ga-LW02050 were 1.20 ± 0.31, 1.39 ± 0.54, and 8.53 ± 1.52 nM, respectively. Both Ga-LW02075 and Ga-LW02050 were confirmed to be GRPR antagonists by calcium release assay. Imaging studies showed that PC-3 prostate cancer tumor xenografts were clearly visualized at 1 h post injection by [68Ga]Ga-SB3 and [68Ga]Ga-LW02050 in PET images, but not by [68Ga]Ga-LW02075. Ex vivo biodistribution studies conducted at 1 h post injection showed that the tumor uptake of [68Ga]Ga-LW02050 was comparable to that of [68Ga]Ga-SB3 (5.38 ± 1.00 vs. 6.98 ± 1.36 %ID/g), followed by [68Ga]Ga-LW02075 (3.97 ± 1.71 %ID/g). [68Ga]Ga-SB3 had the highest pancreas uptake (37.3 ± 6.90 %ID/g) followed by [68Ga]Ga-LW02075 (17.8 ± 5.24 %ID/g), while the pancreas uptake of [68Ga]Ga-LW02050 was only 0.53 ± 0.11 %ID/g. Our data suggest that [68Ga]Ga-LW02050 is a promising PET tracer for detecting GRPR-expressing cancer lesions.
摘要：
胃泌素释放肽受体(GRPR),在许多实体瘤中过度表达，是一个很有前途的成像标记和治疗靶点。大多数报道的GRPR靶向放射性配体含有C末端酰胺。根据报道的强效拮抗剂D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH，我们合成了C末端异羟肟酸盐衍生的[68Ga]Ga-LW02075([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH)和[68Ga]Ga-LW02050([68Ga]-DOTA-Pip-D-NHal-Phe-并将它们与密切相关和临床验证的[68Ga]Ga-SB3([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt)进行了比较。Ga-SB3、Ga-LW02075和Ga-LW02050的结合亲和力（Ki）分别为1.20±0.31、1.39±0.54和8.53±1.52nM，分别。通过钙释放测定证实Ga-LW02075和Ga-LW02050都是GRPR拮抗剂。影像学研究表明，在PET图像中，[68Ga]Ga-SB3和[68Ga]Ga-LW02050注射后1小时，PC-3前列腺癌肿瘤异种移植物清晰可见。但不是[68Ga]Ga-LW02075。注射后1小时进行的离体生物分布研究表明，[68Ga]Ga-LW02050的肿瘤摄取与[68Ga]Ga-SB3相当（5.38±1.00vs.6.98±1.36%内径/g)，然后是[68Ga]Ga-LW02075(3.97±1.71%ID/g)。[68Ga]Ga-SB3的胰腺摄取最高（37.3±6.90%ID/g），其次是[68Ga]Ga-LW02075（17.8±5.24%ID/g），而[68Ga]Ga-LW02050的胰腺摄取仅为0.53±0.11%ID/g。我们的数据表明[68Ga]Ga-LW02050是一种有前途的PET示踪剂，可用于检测表达GRPR的癌症病变。
