European journal of nuclear medicine and molecular imaging · 2025
Preclinical evaluation and first-in-human study of 68Ga- and Al18F-Labeled PSMA/FAP bispecific tracers for prostate cancer imaging.
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Wang Xinlin, Wang Ming, Chen Yimin, Jian Ruotong, Yu Haonan, Zhang Xiaojun, Zhang Jinming, Yao Shaobo, Du Jin, Cui Mengchao
Аннотация
PURPOSE: Prostate-specific membrane antigen (PSMA) expression may decrease during the progression of prostate cancer (PCa), compromising the efficacy of PSMA-targeted imaging. Fibroblast activation protein (FAP), a key component of the tumor microenvironment, offers a complementary target. This study aimed to develop and evaluate PSMA/FAP bispecific tracers with a biphenyl scaffold for improved PET detection outcomes of PCa.
METHODS: The binding affinities of precursors and their corresponding non-radioactive standards were assessed using recombinant PSMA and FAP proteins. PET/CT imaging was performed in 22Rv1 (PSMA-positive) and U87MG (FAP-positive) xenograft models. Clinical evaluation of [18F]AlF-NOTA-PSFA-1 was conducted in two PCa patients, directly compared with [68Ga]Ga-PSMA-11.
RESULTS: All precursors and their corresponding non-radioactive standards exhibited high affinity for both PSMA (Ki = 0.13-4.86 nM) and FAP (Ki = 0.012-0.40 nM). Among them, [18F]AlF-NOTA-PSFA-1, demonstrated the highest tumor uptake in both 22RV1 (SUVmax = 4.64) and U87MG (SUVmax = 7.23) models, along with favorable tumor retention over time. Compared to [68Ga]Ga-PSMA-11, [18F]AlF-NOTA-PSFA-1 showed higher lesion uptake, reduced background accumulation in off-target organs, and improved imaging quality in metastatic PCa patient.
CONCLUSIONS: The biphenyl-based bispecific tracers developed in this study achieved high tumor affinity, prolonged retention, and notably reduced renal uptake in mouse models. [18F]AlF-NOTA-PSFA-1 emerged as the most promising candidate, demonstrating superior imaging performance over [68Ga]Ga-PSMA-11 in both preclinical and first-in-human evaluation.
TRIAL REGISTRATION: Clinical trial registry NCT06690970, Registered 14 Nov 2024.
METHODS: The binding affinities of precursors and their corresponding non-radioactive standards were assessed using recombinant PSMA and FAP proteins. PET/CT imaging was performed in 22Rv1 (PSMA-positive) and U87MG (FAP-positive) xenograft models. Clinical evaluation of [18F]AlF-NOTA-PSFA-1 was conducted in two PCa patients, directly compared with [68Ga]Ga-PSMA-11.
RESULTS: All precursors and their corresponding non-radioactive standards exhibited high affinity for both PSMA (Ki = 0.13-4.86 nM) and FAP (Ki = 0.012-0.40 nM). Among them, [18F]AlF-NOTA-PSFA-1, demonstrated the highest tumor uptake in both 22RV1 (SUVmax = 4.64) and U87MG (SUVmax = 7.23) models, along with favorable tumor retention over time. Compared to [68Ga]Ga-PSMA-11, [18F]AlF-NOTA-PSFA-1 showed higher lesion uptake, reduced background accumulation in off-target organs, and improved imaging quality in metastatic PCa patient.
CONCLUSIONS: The biphenyl-based bispecific tracers developed in this study achieved high tumor affinity, prolonged retention, and notably reduced renal uptake in mouse models. [18F]AlF-NOTA-PSFA-1 emerged as the most promising candidate, demonstrating superior imaging performance over [68Ga]Ga-PSMA-11 in both preclinical and first-in-human evaluation.
TRIAL REGISTRATION: Clinical trial registry NCT06690970, Registered 14 Nov 2024.