Design, preclinical evaluation, and first-in-human PET study of [68Ga]Ga-PSFA-01: a PSMA/FAP heterobivalent tracer

IF 8.6 1区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

European Journal of Nuclear Medicine and Molecular Imaging Pub Date : 2024-11-09 DOI:10.1007/s00259-024-06965-7

Xinlin Wang, Xiaoyang Zhang, Xiaojun Zhang, Lili Guan, Xi Gao, Lu Xu, Hua Pang, Jin Du, Jinming Zhang, Mengchao Cui

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引用次数: 0

Abstract

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 [^natGa]Ga-PSFA-01 was evaluated in vitro. Micro-PET/CT imaging was performed on 22Rv1 and U87MG tumor-bearing mice. The feasibility of [⁶⁸Ga]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 [⁶⁸Ga]Ga-FAPI-04 and [⁶⁸Ga]Ga-PSMA-11 PET/CT.

Results

PSFA-01 and [^natGa]Ga-PSFA-01 showed high affinity for both FAP and PSMA proteins (K_i = 0.14–1.02 nM). On micro-PET/CT imaging, the 22Rv1 tumor uptake of [⁶⁸Ga]Ga-PSFA-01 (SUV_max = 3.89 ± 0.47) was higher than that of [⁶⁸Ga]Ga-PSMA-11 (SUV_max = 2.96 ± 0.48). The U87MG tumor uptake of [⁶⁸Ga]Ga-PSFA-01 was significantly higher (SUV_max = 7.29 ± 1.13) than [⁶⁸Ga]Ga-FAPI-04 (SUV_max = 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 [⁶⁸Ga]Ga-PSFA-01 (21 lesions), demonstrating superior performance compared to [⁶⁸Ga]Ga-FAPI-04 (3 lesions) and [⁶⁸Ga]Ga-PSMA-11 (13 lesions) in terms of lesion count and specificity.

Conclusions

[⁶⁸Ga]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 [⁶⁸Ga]Ga-PSFA-01 PET/CT for detecting metastatic tumors of prostate cancer more sensitively compared to monomeric [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]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.

Abstract Image

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68Ga]Ga-PSFA-01：一种 PSMA/FAP 异价示踪剂的设计、临床前评估和首次人体 PET 研究

目的前列腺癌（PCa）具有肿瘤异质性的特点，癌灶中可能会出现前列腺特异性膜抗原（PSMA）低表达或不表达的情况，从而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）经常在肿瘤微环境（TME）中过度表达，我们开发了一种 PSMA/FAP 双靶向示踪剂来解决这一局限性。方法前体（PSFA-01）是通过酰胺键将基于喹诺酮的 FAP 靶向支架和 EuK 与 HBED-CC 连接合成的。体外评估了 PSFA-01 和 [natGa]Ga-PSFA-01 的双受体结合亲和力和细胞摄取能力。在22Rv1和U87MG肿瘤小鼠身上进行了显微PET/CT成像。在一名转移性前列腺癌患者身上评估了[68Ga]Ga-PSFA-01 PET/CT在临床环境中的可行性，并将结果与[68Ga]Ga-FAPI-04和[68Ga]Ga-PSMA-11 PET/CT的结果进行了比较。在显微PET/CT成像中，22Rv1肿瘤对[68Ga]Ga-PSFA-01的摄取（SUVmax = 3.89 ± 0.47）高于[68Ga]Ga-PSMA-11（SUVmax = 2.96 ± 0.48）。U87MG肿瘤对[68Ga]Ga-PSFA-01的摄取量（SUVmax = 7.29 ± 1.13）明显高于[68Ga]Ga-FAPI-04（SUVmax = 0.28 ± 0.12）。在临床试验中，[68Ga]Ga-PSFA-01（21个病灶）能明显识别原发肿瘤和转移病灶，与[68Ga]Ga-FAPI-04（3个病灶）和[68Ga]Ga-PSMA-11（13个病灶）相比，[68Ga]Ga-PSFA-01在病灶数量和特异性方面表现出更优越的性能。与单体[68Ga]Ga-PSMA-11和[68Ga]Ga-FAPI-04相比，本研究强调了[68Ga]Ga-PSFA-01 PET/CT检测前列腺癌转移性肿瘤的临床可行性，这也表明PSMA/FAP双靶向放射性核素疗法有可能克服与PCa中肿瘤异质性和PSMA表达不足有关的挑战。

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来源期刊

European Journal of Nuclear Medicine and Molecular Imaging 医学-核医学

CiteScore

15.60

自引率

9.90%

发文量

392

审稿时长

3 months

期刊介绍： The European Journal of Nuclear Medicine and Molecular Imaging serves as a platform for the exchange of clinical and scientific information within nuclear medicine and related professions. It welcomes international submissions from professionals involved in the functional, metabolic, and molecular investigation of diseases. The journal's coverage spans physics, dosimetry, radiation biology, radiochemistry, and pharmacy, providing high-quality peer review by experts in the field. Known for highly cited and downloaded articles, it ensures global visibility for research work and is part of the EJNMMI journal family.