Abstract
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Introduction: Bruton's tyrosine kinase (BTK) is a key component of B-cell receptor signaling (BCR), 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 report for the first time the development of a novel BTK PET tracer with the potential for imaging of target expression and/or target engagement (by small molecule therapeutics).
Methods: Radiochemistry was carried out by reacting the precursor with [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]ABBV-BTK1 with a 6% decay-corrected radiochemical yield, >3000 Ci/mmol specific activity, and a radiochemical purity of 99%.Following i.v. administration of [18F]ABBV-BTK1 (120±17 µCi, 0.084±0.05 µg) 60 minute dynamic images were acquired on an Inveon PET/CT system, in two xenograft models: REC-1 (n=6), an efficacious mantle cell lymphoma model, and U87MG (n=6), 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 a reversible BTK inhibitor to examine BTK binding. Regions of interest were manually delineated in the tumor and left ventricle and time activity curves were generated. Estimates of volume of distribution (VT) of the tracer (defined as the ratio of the tracer concentration in tumor (CT, kBq·cm-3) to that in plasma (CP, kBq·mL-1) at equilibrium) were obtained using a metabolite-corrected image-derived input function and kinetic modeling.
Results: VT, representing uptake of [18F]ABBV-BTK1, was significantly higher in BTK expressing REC-1 tumors (4.0±1.6) than non-BTK expressing U87MG tumors (0.5±0.13). Administration of BTK inhibitors reduced [18F]ABBV-BTK1 binding in the REC-1 tumor model consistent with [18F]ABBV-BTK1 binding to BTK.
Conclusions: [18F]ABBV-BTK1 is a promising PET tracer candidate for PET imaging of BTK. Additional experiments are being conducted to further characterize tracer binding in vivo and explore potential clinical applications including assessment of target engagement. [asterisk]Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.