Brain exposure of the ATM inhibitor AZD1390 in humans—a positron emission tomography study

Abstract

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.

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

“…So far, most DDRi have been directly radiolabeled with 123 I-, 131 I-, 18 F- and 211 At-radionuclides. Only one analog of olaparib was 64 Cu-radiolabeled following conjugation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) moiety, allowing for PET imaging of mesothelioma [ 29 , 40 , 49 , 50 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ].…”

“…In macaque monkeys, intravenous administration revealed superior permeability and BBB penetrating properties of [ 11 C]-AZD1390 compared to [ 11 C]-AZD0156 [ 75 ]. A first clinical trial in healthy volunteers analyzed the brain distribution of [ 11 C]-AZD1390 and confirmed BBB penetration [ 59 ]. These findings support the use of radiolabeled AZD1390 for therapy and/or diagnostics in patients with central nervous system (CNS) malignancies, including GB.…”

“…AZD1390 has been converted to a 11 C-radiolabeled drug that showed good BBB penetration (1% ID at T max [brain] = 21 min) in healthy volunteers. Results on the aspects of safety, tolerability, and pharmacokinetics of [ 11 C]-AZD1390 in combination with RT are expected by 2024 [ 29 , 59 ]. The fast localization of AZD1390 to the brain limits the use of AZD1390 in TRT to those therapeutic radionuclides that match its biodistribution characteristics.…”

Therapeutic Opportunities of Disrupting Genome Integrity in Adult Diffuse Glioma

“…KU-55933 was the first specific ATM inhibitor being developed. Subsequent improvement includes KU-60019, CP46722 and KU-59403, but none of these inhibitors are able to penetrate the blood-brain barrier (BBB) except for AstraZeneca’s experimental AZ32 compound, which was further optimized in becoming the first-in-class oral ATM inhibitor, AZD1390 [ 52 ]. In the context of therapeutic targeting, inhibition of ATM activity in PTEN-deficient tumors with an already diminished HR can prevent repair compensation, resulting in unresolved DSBs [ 53 ].…”

Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

“…ATRN-119 is a next-generation ATRi with enhanced potency and specificity that is entering early-phase trials [ 149 ]. Four ATM inhibitors, including the brain-penetrant, oral AZD1390 [ 150 ], are being studied in six trials. Five DNA-PK inhibitors are in early-phase trials.…”