Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton’s Tyrosine Kinase

• Published in: ACS pharmacology & translational science Vol. 6; no. 3; pp. 410 - 421
• Main Authors: Li, Kaixuan, Wang, Mingqian, Akoglu, Melike, Pollard, Alyssa C., Klecker, John B., Alfonso, Patricia, Corrionero, Ana, Prendiville, Niall, Qu, Wenchao, Parker, Matthew F. L., Turkman, Nashaat, Cohen, Jules A., Tonge, Peter J.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.03.2023
• Subjects: BTK; fluorine-18; Jeko-1; PET imaging; tumor; U87MG
• ISSN: 2575-9108; 2575-9108
• DOI: 10.1021/acsptsci.2c00215

Bruton’s tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases. To aid in the discovery and development of BTK inhibitors and improve clinical diagnoses, we have developed a positron emission tomography (PET) radiotracer based on a selective BTK inhibitor, remibrutinib. [18F]­PTBTK3 is an aromatic, 18F-labeled tracer that was synthesized in 3 steps with a 14.8 ± 2.4% decay-corrected radiochemical yield and ≥99% radiochemical purity. The cellular uptake of [18F]­PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [18F]­PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/​severe combined immunodeficiency) mice, and the tumor uptake of [18F]­PTBTK3 in BTK-positive JeKo-1 xenografts (1.23 ± 0.30% ID/cc) was significantly greater at 60 min post injection compared to the tumor uptake in BTK-negative U87MG xenografts (0.41 ± 0.11% ID/cc). In the JeKo-1 xenografts, tumor uptake was blocked up to 62% by remibrutinib, indicating the BTK-dependent uptake of [18F]­PTBTK3 in tumors.