Development and labeling of EP-00652218 analogues, NK1 receptors antagonist, for PET and SPECT imaging

The aim of this work was the synthesis and radiosynthesis of compounds labelled either with a positron emitter (fluorine-18, t1/2 = 109 minutes) or with a gamma emitter (iodine-123, t1/2 = 16.2 hours), for Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) studies. EP-00652218 is a novel potent antagonist, with a sub-nano-molar affinity towards the NK1 receptors. In order to develop ligands that could be used either in PET or SPECT, we undertook the synthesis of poly-halogenated analogues of EP-00652218. Compound 17 was synthesized through two different synthetic pathways. A series of original compounds has been obtained from compound 17 by halogen exchanges on the naphthyridone or the benzene ring. These molecules were tested to determine their in vitro affinity towards NK1 receptors. Compound 21 was labelled with fluorine-18 in 135 minutes and with a 20% radiochemical yield. Compound 26 was radioiodinated following reaction with Na125I (t1/2 = 60.14 days) in a 18% radiochemical yield. Despite expectation, these analogues of EP-00652218 exhibited an insufficient affinity for NK1 receptors (IC50 = 10-7 M) and thus unlikely usable for in vivo studies with PET and SPECT. (author)