Radiofluorinated Analogs of NCS-382 as Potential PET Tracers for Imaging the CaMKIIα Hub Domain

The Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a key regulator of calcium signaling in the central nervous system and is suggested to play a crucial role in neurodegenerative diseases and stroke. The CaMKIIα hub domain was recently identified as a high-affinity binding site for γ-hydroxybutyric acid (GHB), representing a new target for neurological research and therapy. In this study, we synthesized and evaluated two novel radiofluorinated GHB analogs, [¹⁸F]6 and [¹⁸F]9, to visualize CaMKIIα via this domain in vivo using positron emission tomography (PET). In vitro autoradiography demonstrated specific binding of [¹⁸F]6 to CaMKIIα-rich brain regions, whereas [¹⁸F]9 exhibited apparent nonspecific myelin binding. In vivo, [¹⁸F]6 crossed the blood-brain barrier but did not exhibit effective PET imaging of CaMKIIα presumably due to a too low affinity. Despite this limitation, the brain penetrance of the compound suggests that further chemical modifications could enhance its suitability for neuroimaging. This work provides a foundation for future radiotracer development targeting CaMKIIα.