Synthesis, Radiolabeling, and In Vivo Pharmacokinetic Evaluation of the Amyloid Beta Radioligand [11C]AZD4694 in Nonhuman Primates

Abstract

[(18)F]AZD4694 (2-(2-(18)F-fluoro-6-(methylamino)-3-pyridyl)benzofuran-5-ol) is a radioligand suitable for imaging of amyloid beta deposits in the living human brain using positron emission tomography (PET). Here, we report the preparation and pharmacokinetic profile of its carbon-11 (t1/2 = 20.4 min) labeled isotopolog [(11)C]AZD4694 and compare [(11)C]AZD4694 with the hitherto most widely applied amyloid PET radioligand [(11)C]Pittsburgh Compound B (PiB). The immediate unlabeled precursor to [(11)C]AZD4694 was prepared in a four-step convergent synthesis. Subsequent N-(11)C-methylation of this precursor with [(11)C]methyl iodide yielded [(11)C]AZD4694, which after isolation and formulation was injected into cynomolgus monkeys. The radioactivity in nonhuman primate brain following injection of [(11)C]AZD4694 and [(11)C]PiB was measured using PET. [(11)C]AZD4694 was prepared in a 60 % incorporation yield. In a head to head comparison with [(11)C]PiB, it appeared that [(11)C]AZD4694 displayed slightly lower nonspecific binding in white matter than [(11)C]PiB as well as more rapid pharmacokinetics in the brain. The advantageous pharmacokinetic profile and low nonspecific binding render [(11)C]AZD4694 a promising PET radioligand for imaging of amyloid beta in the human brain with PET.