Development and Evaluation in Rat and Monkey of a Candidate Homochiral Radioligand for PET Studies of Brain Receptor Interacting Protein Kinase 1: [F]()-1-(5-(3-Fluorophenyl)-4,5-dihydro-1-pyrazol-1-yl)-2,2-dimethylpropan-1-one.

Receptor interacting protein kinase 1 (RIPK1) crucially upregulates necroptosis and is a key driver of inflammation. An effective PET radioligand for imaging brain RIPK1 would be useful for further exploring the role of this enzyme in neuroinflammation and for assisting drug discovery. Here, we report our progress on developing a PET radioligand for RIPK1 based on the phenyl-1-dihydropyrazole skeleton of a lead RIPK1 inhibitor, GSK'963. The most potent inhibitor from a small structure-activity relationship study,()-1-(5-(3-fluorophenyl)-4,5-dihydro-1-pyrazol-1-yl)-2,2-dimethylpropan-1-one (()- or ()-), was labeled with no-carrier-added fluorine-18 ( = 109.8 min) from a homochiral -tri--butylstannane precursor [()-] in 10-15% formulated yields. The lipophilicity measured for F- was moderate (log = 3.00) and conducive to good brain permeability. PET scans with F- in healthy monkeys under baseline and preblock conditions with a RIPK1 inhibitor, either Nec-1s or GSK'963, demonstrated high peak radioactivity uptake in the brain (3.1-3.9 SUV) but no evidence of RIPK1-specific binding. Moreover, F- did not detect neuroinflammation in rats on day 1 and day 8 after systemic lipopolysaccharide administration. We conclude that F- is unpromising for imaging human brain RIPK1 in neuroinflammation. Higher-affinity radioligands may be needed for this purpose.