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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 [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]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 [18F]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 [18F]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 [18F]BTK-1 binding in the REC-1 tumor model consistent with [18F]BTK-1 binding to BTK. The predicted effective dose in humans was 0.0199 ± 0.0007 mSv/MBq. Conclusion: [18F]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]

Mass balance, metabolism, and excretion of ABT-126, an α 7 neuronal acetylcholine receptor agonist, were characterized in healthy male subjects ( n = 4) after a single 100-mg (100 μ Ci) oral dose. The total recovery of the administered radioactivity was 94.0% (±2.09%), with 81.5% (±10.2%) in urine and 12.4% (±9.3%) in feces. Metabolite profiling indicated that ABT-126 had been extensively metabolized, with 6.6% of the dose remaining as unchanged parent drug in urine. Parent drug accounted for 12.2% of the administered radioactivity in feces. The primary metabolic transformations of ABT-126 involved aza-adamantane N -oxidation (M1, 50.3% in urine) and aza-adamantane N -glucuronidation (M11, 19.9% in urine). M1 and M11 were also major circulating metabolites, accounting for 32.6% and 36.6% of the drug-related material in plasma, respectively. These results demonstrated that ABT-126 is eliminated primarily by hepatic metabolism, followed by urinary excretion. Enzymatic studies suggested that M1 formation is mediated primarily by human liver flavin-containing monooxygenase (FMO)3 and, to a lesser extent, by human kidney FMO1; M11 is generated mainly by human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4, whereas UGT 2B10 also contributes to ABT-126 glucuronidation. Species-dependent formation of M11 was observed in hepatocytes; M11 was formed in human and monkey hepatocytes, but not in rat and dog hepatocytes, suggesting that monkeys constitute an appropriate model for predicting the fate of compounds undergoing significant N -glucuronidation. M1 and M11 are not expected to have clinically relevant on- or off-target pharmacologic activities. In summary, this study characterized ABT-126 metabolites in the circulation and excreta and the primary elimination pathways of ABT-126 in humans., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)