Development, preclinical evaluation and preliminary dosimetry profiling of SB03178, a first-of-its-kind benzo[h]quinoline-based fibroblast activation protein-α-targeted radiotheranostic for cancer imaging and therapy.

Fibroblast activation protein-α (FAP) is a marker of cancer-associated fibroblasts (CAFs) that constitute a significant portion of most carcinomas. Since it plays a critical role in tumor growth and metastasis, its timely detection to identify tumor lesions in early developmental stages using targeted radiopharmaceuticals has gained significant impetus. In the present work, two novel FAP-targeted precursors SB03178 and SB04033 comprising of an atypical benzo[h]quinoline construct were synthesized and either chelated to diagnostic radionuclide gallium-68 or therapeutic radionuclide lutetium-177, with ≥90% radiochemical purities and 22-76% decay-corrected radiochemical yields. ^nat Ga-labeled complexes displayed dose-dependent FAP inhibition, with binding potency of ^nat Ga-SB03178 being ∼17 times higher than ^nat Ga-SB04033. To evaluate their pharmacokinetic profiles, PET imaging and ex vivo biodistribution analyses were executed in FAP-overexpressing HEK293T:hFAP tumor-bearing mice. While both tracers displayed clear tumor visualization that was primarily FAP-arbitrated, with negligible uptake in most peripheral tissues, [ ⁶⁸ Ga]Ga-SB03178 demonstrated higher tumor uptake and superior tumor-to-background contrast ratios than [ ⁶⁸ Ga]Ga-SB04033. ¹⁷⁷ Lu-labeled SB03178 was subjected to tumor retention studies, mouse dosimetry profiling and mouse-to-human dose extrapolations also using the HEK293T:hFAP tumor model. [ ¹⁷⁷ Lu]Lu-SB03178 exhibited a combination of high and sustained tumor uptake, with excellent tumor-to-critical organ uptake ratios resulting in a high radiation absorbed dose to the tumor and a low estimated whole-body dose to humans. Our preliminary findings are considerably encouraging to support clinical development of [ ⁶⁸ Ga]Ga-/[ ¹⁷⁷ Lu]Lu-SB03178 theranostic pair for use in a vast majority of FAP-overexpressing neoplasms, particularly carcinomas.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kuo-Shyan Lin reports a relationship with Alpha-9 Oncology Inc that includes: consulting or advisory, equity or stocks, and funding grants. Helen Merkens reports a relationship with Alpha-9 Oncology Inc that includes: equity or stocks. Francois Benard reports a relationship with Alpha-9 Oncology Inc that includes: board membership, consulting or advisory, equity or stocks, and funding grants. Hsiou-Ting Kuo reports a relationship with Alpha-9 Oncology Inc that includes: employment and equity or stocks. Zhengxing Zhang reports a relationship with Alpha-9 Oncology Inc that includes: equity or stocks. Kuo-Shyan Lin has patent #PCT/CA2023/050040 pending to Provincial Health Services Authority. Francois Benard has patent #PCT/CA2023/050040 pending to Provincial Health Services Authority. Zhengxing Zhang has patent #PCT/CA2023/050040 pending to Provincial Health Services Authority. Shreya Bendre has patent #PCT/CA2023/050040 pending to Provincial Health Services Authority. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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