Evaluation of specific binding of [11C]TZ7774 to the receptor-interacting protein kinase 1 (RIPK1) in the brain.

Microglia, a type of immune cells of the central nervous system, play a critical role in the pathophysiology of neurodegenerative disorders including Alzheimer's disease (AD). Recently, efforts for drug discovery have focused on modifying the function of microglia to halt AD progression. One such effort targets a multifaceted kinase called receptor-interacting protein kinase 1 (RIPK1) that controls inflammation and cell death. Pharmaceutical inhibition of RIPK1 in microglia prevents their homeostatic status from transforming to disease-associated status. Thus, RIPK1 inhibitors can be a therapeutic agent for halting AD progression. Therefore, in vivo imaging of RIPK1 may be a useful biomarker of AD. Recently, a novel PET ligand, [¹¹C]TZ7774, targeting RIPK1 was developed showing its ability to enter the brain and an increased uptake in the spleen of acute inflammation model mice. However, they have not yet shown direct evidence of specific binding of [¹¹C]TZ7774 to RIPK1 in the brain. In this study, we replicated the synthesis of [¹¹C]TZ7774 and examined its specific binding in the rat and human brain. Our studies with this ligand failed to detect sufficient specific binding of [¹¹C]TZ7774 to RIPK1 in the brain neither by PET imaging with healthy and acute inflammation model rats, nor by autoradiography with healthy rat and human brain slices. Our results suggest that the RIPK1 ligand, [¹¹C]TZ7774, is unlikely to be useful in humans. Future studies are warranted to develop more optimal radioligands for PET imaging of RIPK1.