Abstract
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Objectives The norepinephrine transporter (NET) is a marker for the number or integrity of noradrenergic (NE) terminals in the CNS. Our studies are focused on the discovery and advancement of novel NET PET tracers to determine NET binding potentials in brain.
Methods The de novo design of novel NET inhibitors was realized by using molecular modeling and an iterative structure-activity relationship (SAR) paradigm. A diverse compound series was prepared, competitive binding assays were performed, and ligands with appropriate NET binding affinities were radiolabeled with F-18 or C-11. Initial rhesus monkey PET imaging evaluations were conducted with a Focus-220 scanner to assess tracer in vivo performances and correlations to in vitro binding profiles.
Results The iterative modeling-SAR approach afforded a novel class of isoquinoline-based NET inhibitor agents, including a ligand subset possessing high NET potency (Ki < 10 nM) and selectivity (100x for NET). Four potent NET inhibitors were selected for F-18/C-11 labeling and initial PET imaging evaluation in rhesus monkeys. The tracers had favorable lipophilicity (logP 0.69-1.56) and plasma free fraction (25%-52%) values. In vivo tissue distribution profiles correlated well with in vitro Ki values. Lower affinity radioligands had negligible NET specific binding whereas higher affinity tracers displayed significantly elevated uptake in NET-rich brain regions (e.g., brainstem, thalamus, cingulate cortex) and lowest uptake in the putative NET reference regions of caudate, putamen and occipital cortex. The F-18 tracer with the highest NET binding signals has undergone comprehensive evaluation to determine NET binding potentials in brain.
Conclusions De novo design with iterative SAR is a powerful tool for the discovery and advancement of novel NET PET tracers. Application of this approach will greatly accelerate the discovery and development of novel PET tracers for other neuroimaging targets.
Research Support NIH R33MH06662