Preclinical in vitro and in vivo evaluation of [11C]ORM-13070 as PET ligand for alpha-2C adrenergic receptor occupancy using PET imaging in non-human primates

• Published in: Journal of cerebral blood flow and metabolism Vol. 45; no. 4; pp. 677 - 689
• Main Authors: Piel, Isabel, Constantinescu, Cristian C, de la Puente Bethencourt, David, Bonsall, David R, Rabiner, Eugenii A, Zasadny, Kenneth R, Llopis Amenta, Amy, Wells, Lisa A, Poethko, Thorsten, Prange, Wolfgang, Delbeck, Martina
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.04.2025
• Subjects: Adrenergic alpha-2 Receptor Antagonists - pharmacokinetics; Animals; Autoradiography; Brain - diagnostic imaging; Brain - metabolism; Carbon Radioisotopes; Dioxanes; Female; Humans; Ligands; Macaca fascicularis; Male; Original; Piperazines; Positron-Emission Tomography - methods; Radiopharmaceuticals - pharmacokinetics; Receptors, Adrenergic, alpha-2 - metabolism; receptor occupancy; alpha-2C adrenergic receptor; non-human primate; positron emission tomography; ORM-13070
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1177/0271678X241291949

This paper describes the preclinical validation of the radioligand [11C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α2CR) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α2CR. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [3H]ORM-13070. BAY 292 bound to the same binding site as [3H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α2CR. In non-human primates in vivo, [11C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α2CR. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC50 for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [11C]ORM-13070 as a PET-radioligand for the study of α2CR in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292.