Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211, USA.
Nucl Med Biol. 2010 Oct;37(7):751-61. doi: 10.1016/j.nucmedbio.2010.04.016.
UNLABELLED: Gastrin-releasing peptide receptors (GRPr) are a member of the bombesin (BBN) receptor family. GRPr are expressed in high numbers on specific human cancers, including human prostate cancer. Therefore, copper-64 ((64)Cu) radiolabeled BBN(7-14)NH(2) conjugates could have potential for diagnosis of human prostate cancer via positron-emission tomography (PET). The aim of this study was to produce [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates for prostate cancer imaging, where X=pharmacokinetic modifier (beta-alanine, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 9-aminonanoic acid or para-aminobenzoic acid) and NO2A=1,4,7-triazacyclononane-1,4-diacetic acid [a derivative of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)]. METHODS: [(X)-BBN(7-14)NH(2)] Conjugates were synthesized by solid-phase peptide synthesis (SPPS), after which NOTA was added via manual conjugation. The new peptide conjugates were radiolabeled with (64)Cu radionuclide. The receptor-binding affinity was determined in human prostate PC-3 cells, and tumor-targeting efficacy was determined in PC-3 tumor-bearing severely combined immunodeficient (SCID) mice. Whole-body maximum intensity microPET/CT images of PC-3 tumor-bearing SCID mice were obtained 18 h postinjection (pi). RESULTS: Competitive binding assays in PC-3 cells indicated high receptor-binding affinity for the [NO2A-(X)-BBN(7-14)NH(2)] and [(nat)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates. In vivo biodistribution studies of the [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates at 1, 4 and 24 h pi showed very high uptake of the tracer in GRPr-positive tissue with little accumulation and retention in nontarget tissues. High-quality, high-contrast microPET images were obtained, with xenografted tumors being clearly visible at 18 h pi. CONCLUSIONS: NO2A chelator sufficiently stabilizes copper(II) radiometal under in vivo conditions, producing conjugates with very high uptake and retention in targeted GRPr. Preclinical evaluation of these new peptide conjugates in tumor-bearing mice provides some impetus for clinical evaluation in human patients.
目的：制备用于前列腺癌成像的 [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] 缀合物，其中 X= 药代动力学修饰剂（β-丙氨酸、5-氨基戊酸、6-氨基己酸、8-氨基辛酸、9-氨基壬酸或对氨基苯甲酸）和 NO2A=1,4,7-三氮杂环壬烷-1,4-二乙酸[NOTA（1,4,7-三氮杂环壬烷-1,4,7-三乙酸）的衍生物]。 方法：通过固相肽合成（SPPS）合成 [(X)-BBN(7-14)NH(2)] 缀合物，然后通过手动缀合添加 NOTA。新的肽缀合物用 (64)Cu 放射性核素标记。在人前列腺 PC-3 细胞中测定受体结合亲和力，并在携带 PC-3 肿瘤的严重联合免疫缺陷（SCID）小鼠中测定肿瘤靶向功效。在注射后 18 小时（pi），获得携带 PC-3 肿瘤的 SCID 小鼠的全身最大强度 microPET/CT 图像。 结果：PC-3 细胞中的竞争性结合试验表明，[NO2A-(X)-BBN(7-14)NH(2)] 和 [(nat)Cu-NO2A-(X)-BBN(7-14)NH(2)] 缀合物具有高受体结合亲和力。在 1、4 和 24 h pi 时，[(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] 缀合物的体内生物分布研究表明，在 GRPr 阳性组织中，示踪剂的摄取非常高，而在非靶组织中几乎没有积聚和保留。获得了高质量、高对比度的 microPET 图像，在 18 h pi 时可清楚地看到异种移植肿瘤。 结论：NO2A 螯合剂在体内条件下充分稳定铜（II）放射性金属，产生在靶向 GRPr 中具有非常高摄取和保留的缀合物。这些新的肽缀合物在荷瘤小鼠中的临床前评估为人类患者的临床评估提供了一些动力。
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