Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Arsyangela Verena
ORCID logo ,
Helen Merkens
,
Chao-Cheng Chen
,
Devon E. Chapple
,
Lei Wang
,
Shreya Bendre
,
Antonio A. W. L. Wong
ORCID logo ,
François Bénard
ORCID logo ,
Kuo-Shyan Lin
* ORCID logo
Version 1 : Received: 12 November 2023 / Approved: 13 November 2023 / Online: 13 November 2023 (08:55:55 CET)

A peer-reviewed article of this Preprint also exists.

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: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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