[18F]BTK-1: A Novel Positron Emission Tomography Tracer for Imaging Bruton’s Tyrosine Kinase

• Published in: Molecular imaging and biology 2022-10, Vol.24 (5), p.830-841
• Main Authors: Skaddan, Marc B., Wooten, Dustin W., Wilcox, Kyle C., Voorbach, Martin J., Reuter, David R., Jia, Zhaozhong J., Foster-Duke, Kelly D., Hickson, Jonathan A., Vaidyanathan, Srirajan, Reed, Aimee D., Tovcimak, Ann E., Guo, Qi, Comley, Robert A., Lee, Lance, Finnema, Sjoerd J., Mudd, Sarah R.
• Format: Article
• Language: English
• Subjects: Adult; Agammaglobulinaemia Tyrosine Kinase - chemistry; Agammaglobulinaemia Tyrosine Kinase - metabolism; Animals; Autoimmune diseases; B-cell receptor; Binding; Bruton's tyrosine kinase; Cell proliferation; Cell survival; Dosimeters; Dosimetry; Fluorides; Fluorine isotopes; Glioblastoma; Humans; Image acquisition; Imaging; Inhibitors; Injection; Intravenous administration; Kinases; Lymphoma; Mantle cell lymphoma; Medicine; Medicine & Public Health; Pathogenesis; Positron emission; Positron emission tomography; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Radiation; Radiation dosimetry; Radiochemistry; Radiology; Rats; Receptors, Antigen, B-Cell; Research Article; Signaling; Tomography; Tumors; Tyrosine; Xenografts; Xenotransplantation
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-022-01733-1

Purpose Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signaling, and as such a critical regulator of cell proliferation and survival. Aberrant BCR signaling is important in the pathogenesis of various B cell malignancies and autoimmune disorders. Here, we describe the development of a novel positron emission tomography (PET) tracer for imaging BTK expression and/or occupancy by small molecule therapeutics. Methods Radiochemistry was carried out by reacting the precursor with [ 18 F]fluoride on a GE FX-FN TracerLab synthesis module to produce [ 18 F]BTK-1 with a 6% decay-corrected radiochemical yield, 100 ± 6 GBq/µmol molar activity, and a radiochemical purity of 99%. Following intravenous administration of [ 18 F]BTK-1 (3.63 ± 0.59 MBq, 0.084 ± 0.05 µg), 60-min dynamic images were acquired in two xenograft models: REC-1, an efficacious mantle cell lymphoma model, and U87MG, a non-efficacious glioblastoma model. Subsequent studies included vehicle, pretreatment (10 min prior to tracer injection), and displacement (30 min post-tracer injection) studies with different reversible BTK inhibitors to examine BTK binding. Human radiation dosimetry was estimated based on PET imaging in healthy rats. Results Uptake of [ 18 F]BTK-1 was significantly higher in BTK expressing REC-1 tumors than non-BTK expressing U87MG tumors. Administration of BTK inhibitors prior to tracer administration blocked [ 18 F]BTK-1 binding in the REC-1 tumor model consistent with [ 18 F]BTK-1 binding to BTK. The predicted effective dose in humans was 0.0199 ± 0.0007 mSv/MBq. Conclusion [ 18 F]BTK-1 is a promising PET tracer for imaging of BTK, which could provide valuable information for patient selection, drug dose determination, and improving our understanding of BTK biology in humans.