Synthesis and Evaluation of Radioiodinated [ ¹²⁵ I]7‐Iodo‐5H‐Pyrido[4,3‐B]Indole ([ ¹²⁵ I]CTAU) in Postmortem Human Alzheimer's Disease Brain

The aim of this study was to further understand the tau imaging agent, flortaucipir (T807), by making small modifications and assess its effect on tau protein binding in Alzheimer's disease (AD). Thus, the fluoropyridyl group in T807 was replaced with an iodine atom. We report here the development and preliminary evaluation of [¹²⁵I]7-iodo-5H-pyrido[4,3-B]indole ([¹²⁵I]CTAU) in postmortem AD brain slices. Using molecular docking, binding energies of CTAU indicated weaker tau binding compared with T807. In vitro tau binding assays in AD brain slices measured IC₅₀ of CTAU and T807 as 44 × 10^-9 M and 3.8 × 10^-9 M, respectively. [¹²⁵I]CTAU was synthesized in high radiochemical purity and molar activity (90 TBq/mmole). Binding of [¹²⁵I]CTAU in the AD grey matter (GM) was observed, with lower nonspecific binding in the white matter (GM/WM = 2.3). Tau binding drugs (T807 and MK-6240, 10 μM) were both able to displace ~90% of bound [¹²⁵I]CTAU in AD brain slices. Clorgyline (10 μM), a monoamine oxidase A inhibitor, decreased the binding of [¹²⁵I]CTAU to 72% of total. In AD brain slices, [¹²⁵I]CTAU exhibited a similar binding profile with the tau imaging agent [¹²⁵I]IPPI. Although [¹²⁵I]CTAU appears promising in vitro, any off-target issues need to be further studied to determine its use in AD-related dementias (ADRD).