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

by Selleckchem | Sep 18 2023

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.

Comments:

That's fascinating! It seems that you have developed a PET radiotracer called [18F]PTBTK3, which is based on the selective BTK inhibitor remibrutinib. PET radiotracers are valuable tools in medical research and clinical practice for visualizing and quantifying biological processes in vivo.

The information you provided suggests that [18F]PTBTK3 has been successfully synthesized with a relatively high radiochemical yield and purity. The cellular uptake experiments in JeKo-1 cells, a B-cell malignancy cell line, demonstrated that the uptake of [18F]PTBTK3 was significantly blocked when either remibrutinib or non-radioactive PTBTK3 was used. This finding indicates that the cellular uptake of [18F]PTBTK3 is BTK-dependent, reinforcing its specificity for BTK-positive cells.

In animal studies using NOD SCID mice, [18F]PTBTK3 exhibited clearance through the kidneys and hepatobiliary system, which is important for understanding its pharmacokinetics and potential elimination pathways. Furthermore, when [18F]PTBTK3 was administered to mice with BTK-positive JeKo-1 xenograft tumors and BTK-negative U87MG xenograft tumors, the tumor uptake in JeKo-1 xenografts was significantly higher than in U87MG xenografts at 60 minutes post-injection. This differential uptake suggests that [18F]PTBTK3 can specifically target BTK-positive tumors.

Additionally, the blocking experiments using remibrutinib in JeKo-1 xenografts resulted in a significant reduction in tumor uptake of [18F]PTBTK3, indicating that the tumor uptake is indeed BTK-dependent. This finding strengthens the evidence for the specificity of [18F]PTBTK3 as a radiotracer for imaging BTK-positive tumors.

Overall, your research demonstrates the potential utility of [18F]PTBTK3 as a PET radiotracer for visualizing BTK expression in B-cell malignancies and potentially aiding in the development of BTK inhibitors for therapeutic purposes. It may also have applications in diagnosing and monitoring BTK-related autoimmune diseases.