Preliminary PET imaging of evobrutinib in mouse models of colorectal cancer, SARS‐CoV‐2, and lung damage: Radiosynthesis via base‐aided palladium‐NiXantphos‐mediated 11C‐carbonylation

• Published in: Journal of labelled compounds & radiopharmaceuticals 2024-05, Vol.67 (6), p.235-244
• Main Authors: Boyle, Amanda J, Lindberg, Anton, Tong, Junchao, Zhai, Dongxu, Liu, Fang, Vasdev, Neil
• Format: Article
• Language: English
• Subjects: Animal models; Autoimmune diseases; Autoradiography; Bruton's tyrosine kinase; Cancer; Carbonyls; Colorectal cancer; Colorectal carcinoma; Computed tomography; Coronaviruses; Damage; Kinases; Lipopolysaccharides; Lungs; Medical imaging; Multiple sclerosis; Palladium; Positron emission; Positron emission tomography; Radioactive tracers; Radioactivity; Radiochemistry; Respiratory diseases; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Tomography; Tyrosine; Viral diseases; Xenografts; Xenotransplantation
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.4062

Evobrutinib is a second‐generation, highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in the autoimmune diseases arthritis and multiple sclerosis. Its development as a positron emission tomography (PET) radiotracer has potential for in vivo imaging of BTK in various disease models including several cancers, severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2), and lipopolysaccharide (LPS)‐induced lung damage. Herein, we report the automated radiosynthesis of [11C]evobrutinib using a base‐aided palladium‐NiXantphos‐mediated 11C‐carbonylation reaction. [11C]Evobrutinib was reliably formulated in radiochemical yields of 5.5 ± 1.5% and a molar activity of 34.5 ± 17.3 GBq/μmol (n = 12) with 99% radiochemical purity. Ex vivo autoradiography studies showed high specific binding of [11C]evobrutinib in HT‐29 colorectal cancer mouse xenograft tissues (51.1 ± 7.1%). However, in vivo PET/computed tomography (CT) imaging with [11C]evobrutinib showed minimal visualization of HT‐29 colorectal cancer xenografts and only a slight increase in radioactivity accumulation in the associated time‐activity curves. In preliminary PET/CT studies, [11C]evobrutinib failed to visualize either SARS‐CoV‐2 pseudovirus infection or LPS‐induced injury in mouse models. In conclusion, [11C]evobrutinib was successfully synthesized by 11C‐carbonylation and based on our preliminary studies does not appear to be a promising BTK‐targeted PET radiotracer in the rodent disease models studied herein.