Brain exposure of the ATM inhibitor AZD1390 in humans - a positron emission tomography (PET) study

Background: The protein kinase ATM (ataxia telangiectasia mutated) mediates cellular response to DNA damage induced by radiation. ATM inhibition decreases DNA damage repair in tumor cells and affects tumor growth. AZD1390 is a novel, highly potent, selective ATM inhibitor designed to cross the blood-brain barrier (BBB) and currently evaluated with radiotherapy in a Phase 1 study in patients with brain malignancies. In the present study, PET was used to measure brain exposure of 11C-labelled AZD1390 after intravenous (i.v.) bolus administration in healthy subjects with an intact BBB.

Methods: AZD1390 was radiolabeled with carbon-11 and a microdose (mean injected mass 1.21µg) was injected in 8 male subjects (21-65 years). The radioactivity concentration of [ 11C]AZD1390 in brain was measured using a high-resolution PET system. Radioactivity in arterial blood was measured to obtain a metabolite corrected arterial input function for quantitative image analysis. Participants were monitored by laboratory examinations, vital signs, ECG, adverse events (AEs).

Results: The brain radioactivity concentration of [ 11C]AZD1390 was 0.64 SUV (standard uptake value) and reached maximum 1.00 %ID (percent of injected dose) at Tmax[brain] of 21 min (time of maximum brain radioactivity concentration) after i.v. injection. The whole brain total distribution volume was 5.20 mL*cm -3. No AEs related to [ 11C]AZD1390 were reported.

Conclusions: This study demonstrates that [ 11C]AZD1390 crosses the intact BBB and supports development of AZD1390 for the treatment of glioblastoma multiforme (GBM) or other brain malignancies. Moreover, it illustrates the potential of PET microdosing in predicting and guiding dose range and schedule for subsequent clinical studies.

Related Products

Cat.No. Product Name Information
S8680 AZD1390 AZD1390 is a first-in-class orally available and CNS penetrant ATM inhibitor with an IC50 of 0.78 nM in cells and >10,000-fold selectivity over closely related members of the PIKK family of enzymes and excellent selectivity across a broad panel of kinases.

Related Targets

3C-Like Protease