1. [18F]BTK-1: A Novel Positron Emission Tomography Tracer for Imaging Bruton's Tyrosine Kinase.
- Author
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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., and Mudd, Sarah R.
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POSITRON emission tomography ,B cells ,GENE expression ,GLIOBLASTOMA multiforme ,ENZYME inhibitors - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2022
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