Development and Evaluation in Rat and Monkey of a Candidate Homochiral Radioligand for PET Studies of Brain Receptor Interacting Protein Kinase 1: [18F](S)-1-(5-(3-Fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one.

Abstract

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-1H-dihydropyrazole skeleton of a lead RIPK1 inhibitor, GSK'963. The most potent inhibitor from a small structure-activity relationship study,(S)-1-(5-(3-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one ((S)-SJ1058 or (S)-5d), was labeled with no-carrier-added fluorine-18 (t_1/2 = 109.8 min) from a homochiral meta-tri-n-butylstannane precursor [(S)-11c] in 10-15% formulated yields. The lipophilicity measured for [¹⁸F](S)-SJ1058 was moderate (log D_7.4 = 3.00) and conducive to good brain permeability. PET scans with [¹⁸F](S)-SJ1058 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 in vivo RIPK1-specific binding. Moreover, [¹⁸F](S)-SJ1058 did not detect neuroinflammation in rats on day 1 and day 8 after systemic lipopolysaccharide administration. We conclude that [¹⁸F](S)-SJ1058 is unpromising for imaging human brain RIPK1 in neuroinflammation. Higher-affinity radioligands may be needed for this purpose.