The ligand-sensing transcription factor nuclear receptor-related 1 (Nurr1), is thought to mediate neuroprotective activity and is implicated in various neurodegenerative diseases. Nurr1 ligands have been developed as tools to capture the receptor’s potential in vitro and in vivo, but a dedicated brain-targeting agonist has been lacking. Here, we employed the scaffold of the dihydroorotate dehydrogenase (DHODH) inhibitor and strong Nurr1 activator vidofludimus to develop a descendant with a high brain-to-blood ratio. Scaffold-hopping from cyclopentene to thiophene, enhanced fluorination, and replacement of the carboxylic acid by an amide provided a highly potent, selective, and brain-penetrant Nurr1 agonist to study the effects of Nurr1 activation in the central nervous system (CNS).