Brain exposure of the ATM inhibitor AZD1390 in humans-a positron emission tomography study
Background: The protein kinase ataxia telangiectasia mutated (ATM) mediates cellular reaction to DNA damage caused by radiation. ATM inhibition decreases DNA damage repair in tumor cells and affects tumor growth. AZD1390 is really a novel, highly potent, selective ATM inhibitor made to mix the bloodstream-brain barrier (BBB) and presently evaluated with radiotherapy inside a phase I study in patients with brain malignancies. In our study, PET was utilized to determine brain exposure of 11C-labeled AZD1390 after intravenous (i.v.) bolus administration in healthy subjects by having an intact BBB.
Methods: AZD1390 was radiolabeled with carbon-11 along with a microdose (mean injected mass 1.21 µg) was injected in 8 male subjects (21-65 y). The radioactivity power of [11C]AZD1390 in brain was measured utilizing a high-resolution PET system. Radioactivity in arterial bloodstream was measured to acquire a metabolite remedied arterial input function for quantitative image analysis. Participants were monitored by laboratory examinations, vital signs, electrocardiogram, adverse occasions.
Results: The mind radioactivity power of [11C]AZD1390 was .64 Sports utility vehicle (standard uptake value) and arrived at maximum 1.00% of injected dose at Tmax[brain] of 21 min (duration of maximum brain radioactivity concentration) once i.v. injection. The entire brain total distribution volume was 5.20 mL*cm-3. No adverse occasions associated with [11C]AZD1390 were reported.
Conclusions: This research shows that [11C]AZD1390 crosses the intact BBB and supports growth and development of AZD1390 to treat glioblastoma multiforme or any other brain malignancies. Furthermore, it illustrates the potential for PET microdosing in predicting and guiding dose range and agenda for subsequent studies.