Quantitative Imaging of ATM: PET and Autoradiography Studies Using [11C]AZD1390.

Abstract

Ataxia-telangiectasia mutated (ATM) kinase plays a crucial role in DNA damage response and has emerged as a promising therapeutic target. AZD1390, an ATM kinase inhibitor developed by AstraZeneca, is currently in phase I clinical trials as a combination therapy with radiation for glioblastoma. Additionally, AZD1390 has been radiolabeled with carbon-11, and its brain penetrability was previously reported. In this study, we investigated in vivo brain uptake and specific binding of [¹¹C]AZD1390 using PET imaging in nonhuman primates (NHP). To assess radiotracer saturability, an in vivo self-competition study was conducted, revealing an unexpected increase in radiotracer uptake after pretreatment with nonradioactive AZD1390, suggesting the involvement of potential efflux mechanisms. Further, in vitro autoradiography studies using competitive and saturation binding using nonhuman primate brain (cortical regions) confirmed the concentration-dependent displaceable and saturable binding of [¹¹C]AZD1390. The binding parameters [K_d (0.23 nM), K_i (0.58 nM), and B_max (267.0 fmol/mg tissue)] demonstrate the high affinity of [¹¹C]AZD1390 and imply that ATM is present at levels (B_max) sufficient for reliable quantification in the brain. While AZD1390 may not be ideal for accurately measuring ATM concentrations due to saturable efflux or other dose nonlinearity mechanisms, these findings support the overall feasibility of quantifying ATM in vivo using PET imaging.