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Synthesis and Preclinical Evaluation of Two Novel 68Ga-labeled Bispecific PSMA/FAP-targeted tracers with 2-Nal-containing PSMA-targeted Pharmacophore and Pyridine-based FAP-targeted Pharmacophore
Verena, A.; Merkens, H.; Chen, C.-C.; Chapple, D.E.; Wang, L.; Bendre, S.; Wong, A.A.W.L.; Bénard, F.; Lin, K.-S. Synthesis and Preclinical Evaluation of Two Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeted Tracers with 2-Nal-Containing PSMA-Targeted Pharmacophore and Pyridine-Based FAP-Targeted Pharmacophore. Molecules 2024, 29, 800, doi:10.3390/molecules29040800.
Verena, A.; Merkens, H.; Chen, C.-C.; Chapple, D.E.; Wang, L.; Bendre, S.; Wong, A.A.W.L.; Bénard, F.; Lin, K.-S. Synthesis and Preclinical Evaluation of Two Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeted Tracers with 2-Nal-Containing PSMA-Targeted Pharmacophore and Pyridine-Based FAP-Targeted Pharmacophore. Molecules 2024, 29, 800, doi:10.3390/molecules29040800.
Verena, A.; Merkens, H.; Chen, C.-C.; Chapple, D.E.; Wang, L.; Bendre, S.; Wong, A.A.W.L.; Bénard, F.; Lin, K.-S. Synthesis and Preclinical Evaluation of Two Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeted Tracers with 2-Nal-Containing PSMA-Targeted Pharmacophore and Pyridine-Based FAP-Targeted Pharmacophore. Molecules 2024, 29, 800, doi:10.3390/molecules29040800.
Verena, A.; Merkens, H.; Chen, C.-C.; Chapple, D.E.; Wang, L.; Bendre, S.; Wong, A.A.W.L.; Bénard, F.; Lin, K.-S. Synthesis and Preclinical Evaluation of Two Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeted Tracers with 2-Nal-Containing PSMA-Targeted Pharmacophore and Pyridine-Based FAP-Targeted Pharmacophore. Molecules 2024, 29, 800, doi:10.3390/molecules29040800.
Abstract
Some bispecific radiotracers have been developed to overcome the limitations of monospecific tracers and improve detection sensitivity for heterogeneous tumor lesions. Here we aim to synthesize two bispecific tracers targeting prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are key markers expressed in prostate cancer. A pyridine-based FAP-targeted ligand was synthesized through multi-step organic synthesis, and then connected to the 2-Nal-containing PSMA-targeted motif. Ki(PSMA) values of Ga-complexed bispecific ligands, Ga-AV01084 and Ga-AV01088, were 11.6 ± 3.25 and 28.7 ± 6.05 nM, respectively, and the IC50(FAP) values of Ga-AV01084 and Ga-AV01088 were 10.9 ± 0.67 and 16.7 ± 1.53 nM, respectively. The uptake values for PSMA-expressing LNCaP tumor xenografts were 9.05 ± 1.54 and 8.85 ± 1.25 %ID/g for [68Ga]Ga-AV010184 and [68Ga]Ga-AV01088, respectively, which were lower than the monospecific PSMA-targeted tracer [68Ga]Ga-PSMA-617 (16.7 ± 2.30 %ID/g). The uptake values for FAP-expressing HEK293T:hFAP tumor xenografts were 1.90 ± 0.41 and 1.20 ± 0.25 %ID/g for [68Ga]Ga-AV01084 and [68Ga]Ga-AV01088, respectively, which were also lower than the monospecific FAP-targeted tracer, [68Ga]Ga-AV02070 (7.93 ± 1.88 %ID/g). Further investigations are needed to optimize the selection of linkers and targeted pharmacophores to improve the tumor uptake of PSMA/FAP bispecific tracers for prostate cancer imaging.
Keywords
Bispecific radiotracers; PSMA; FAP; PET/CT; Gallium-68; prostate cancer
Subject
Chemistry and Materials Science, Medicinal Chemistry
Copyright:
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