GB5121 was designed to be a brain-penetrant BTKi; a PET imaging study confirms the results of previously conducted NHP PK studies demonstrating CNS penetration of GB5121. In a novel model of intracranial lymphoma, treatment with GB5121 resulted in better anti-tumor activity compared to ibrutinib, likely resulting from higher brain penetration and TO. This higher brain penetration and TO exhibited by GB5121 may result in more durable responses in malignancies with CNS involvement and supports the investigation of GB5121 in clinical trials for CNS lymphomas.