[镓]Ga-PSFA-01的设计、临床前评估及首次人体PET研究：一种PSMA/FAP异二价示踪剂
Design, preclinical evaluation, and first-in-human PET study of [Ga]Ga-PSFA-01: a PSMA/FAP heterobivalent tracer.
作者信息
Wang Xinlin, Zhang Xiaoyang, Zhang Xiaojun, Guan Lili, Gao Xi, Xu Lu, Pang Hua, Du Jin, Zhang Jinming, Cui Mengchao
机构信息
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Department of Nuclear Technology and Application, China Institute of Atomic Energy, Beijing, 102413, China.
出版信息
Eur J Nucl Med Mol Imaging. 2025 Feb;52(3):1166-1176. doi: 10.1007/s00259-024-06965-7. Epub 2024 Nov 9.
PURPOSE
Prostate cancer (PCa), characterized by tumor heterogeneity, may exhibit low or absent prostate-specific membrane antigen (PSMA) expression in cancerous lesions, limiting the detection sensitivity of monospecific probes. Given that fibroblast activation protein (FAP) is frequently overexpressed in the tumor microenvironment (TME), we developed a PSMA/FAP dual-targeting tracer to address this limitation.
METHODS
The precursor (PSFA-01) was synthesized by coupling a quinolone-based FAP-targeting scaffold and EuK with HBED-CC via amide bonds. The dual-receptor-binding affinity and cell uptake of PSFA-01 and [Ga]Ga-PSFA-01 was evaluated in vitro. Micro-PET/CT imaging was performed on 22Rv1 and U87MG tumor-bearing mice. The feasibility of [Ga]Ga-PSFA-01 PET/CT in a clinical setting was evaluated in a metastatic prostate cancer patient, and the results were compared with those of [Ga]Ga-FAPI-04 and [Ga]Ga-PSMA-11 PET/CT.
RESULTS
PSFA-01 and [Ga]Ga-PSFA-01 showed high affinity for both FAP and PSMA proteins (K = 0.14-1.02 nM). On micro-PET/CT imaging, the 22Rv1 tumor uptake of [Ga]Ga-PSFA-01 (SUV = 3.89 ± 0.47) was higher than that of [Ga]Ga-PSMA-11 (SUV = 2.96 ± 0.48). The U87MG tumor uptake of [Ga]Ga-PSFA-01 was significantly higher (SUV = 7.29 ± 1.13) than [Ga]Ga-FAPI-04 (SUV = 0.28 ± 0.12), showing tumor to muscle ratio as 12.68 ± 1.93 at 1 h p.i. On clinical trial, the primary tumor and metastatic lesions were distinctly identified by [Ga]Ga-PSFA-01 (21 lesions), demonstrating superior performance compared to [Ga]Ga-FAPI-04 (3 lesions) and [Ga]Ga-PSMA-11 (13 lesions) in terms of lesion count and specificity.
CONCLUSIONS
[Ga]Ga-PSFA-01 exhibited satisfactory PSMA and FAP dual-receptor-targeting properties both in vitro and in vivo. This study highlights the clinical feasibility of [Ga]Ga-PSFA-01 PET/CT for detecting metastatic tumors of prostate cancer more sensitively compared to monomeric [Ga]Ga-PSMA-11 and [Ga]Ga-FAPI-04, which also suggests that a PSMA/FAP dual-targeted radionuclide therapy could potentially overcome challenges related to tumor heterogeneity and insufficient PSMA expression in PCa.
TRIAL REGISTRATION
Clinical trial registry NCT06387381, Registered 1 May 2024.
目的
前列腺癌（PCa）具有肿瘤异质性，其癌性病变中可能表现出低水平或无前列腺特异性膜抗原（PSMA）表达，这限制了单特异性探针的检测灵敏度。鉴于成纤维细胞活化蛋白（FAP）在肿瘤微环境（TME）中经常过度表达，我们开发了一种PSMA/FAP双靶向示踪剂来解决这一限制。
方法
通过酰胺键将基于喹诺酮的FAP靶向支架和EuK与HBED-CC偶联，合成前体（PSFA-01）。在体外评估PSFA-01和[Ga]Ga-PSFA-01的双受体结合亲和力和细胞摄取。对荷22Rv1和U87MG肿瘤的小鼠进行微型PET/CT成像。在一名转移性前列腺癌患者中评估[Ga]Ga-PSFA-01 PET/CT在临床环境中的可行性，并将结果与[Ga]Ga-FAPI-04和[Ga]Ga-PSMA-11 PET/CT的结果进行比较。
结果
PSFA-01和[Ga]Ga-PSFA-表现出对FAP和PSMA蛋白的高亲和力（K = 0.14 - 1.02 nM）。在微型PET/CT成像中，[Ga]Ga-PSFA-01对22Rv1肿瘤的摄取（SUV = 3.89 ± 0.47）高于[Ga]Ga-PSMA-11（SUV = 2.96 ± 0.48）。[Ga]Ga-PSFA-01对U87MG肿瘤的摄取显著高于[Ga]Ga-FAPI-04（SUV = 0.28 ± 0.12），在注射后1小时肿瘤与肌肉的比值为12.68 ± 1.93。在临床试验中，[Ga]Ga-PSFA-01能清晰识别原发性肿瘤和转移灶（21个病灶），在病灶数量和特异性方面显示出优于[Ga]Ga-FAPI-04（3个病灶）和[Ga]Ga-PSMA-11（13个病灶）的性能。
结论
[Ga]Ga-PSFA-01在体外和体内均表现出令人满意的PSMA和FAP双受体靶向特性。本研究强调了[Ga]Ga-PSFA-01 PET/CT相较于单体[Ga]Ga-PSMA-11和[Ga]Ga-FAPI-04在更灵敏检测前列腺癌转移瘤方面的临床可行性，这也表明PSMA/FAP双靶向放射性核素治疗可能克服与PCa中肿瘤异质性和PSMA表达不足相关的挑战。
试验注册
临床试验注册号NCT06387381，于2024年5月1日注册。
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