Radioligand Development

Contact person: Hanne D. Hansen

Positron Emission Tomography (PET) has unsurpassed sensitivity and specificity for measuring neurotransmitter receptors or other protein targets in the living human brain. At NRU we attempt to develop PET radioligands that enable novel and functional measures of different members of the serotonin receptor family. We also evaluate novel radioligands for other neurotransmitter receptors such as the α7 nicotinic receptor and GABAA receptor. Recently, we have engaged in measuring enzymatic proteins such as phosphodiesterases and histone deacetylases allowing us to investigate signal transduction and epigenetic mechanisms, respectively.

The process of PET radioligand development is a time and resource-demanding task that resembles that of pharmaceutical drug development in that promising compounds may fail at any stage of the sequential development process. The development process draws on highly specialized knowledge from fields such as medicinal chemistry, radiochemistry, and in vivo pharmacology. The phases that a PET radioligand for a given target undergoes involve: 1) chemical synthesis of cold ligands and in vitro test of which receptors the molecules bind to, 2) radiolabeling to incorporate a positron emitting isotope into the molecule, 3) in vitro and in vivo evaluation by testing the radiolabeled compound in the living brain of an experimental animal such as rats and pigs with PET.

The compounds that we develop into radioligands are obtained from our close collaboration partner at the Department of Drug Design and Pharmacology at University of Copenhagen, other academic groups around the world or through collaboration from with industry partners.

Examples of recent publications:

  • Donat CK, Hansen HH, Hansen HD, Mease RC, Horti AG, Pomper MG, L'Estrade ET, Herth MM, Peters D, Knudsen GM, Mikkelsen JD. In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors. Molecules. 2020 Mar 20;25(6):1425. doi: 10.3390/molecules25061425. PMID: 32245032; PMCID: PMC7144377.
  • L'Estrade ET, Hansen HD, Falk-Petersen C, Haugaard A, Griem-Krey N, Jung S, Lüddens H, Schirmeister T, Erlandsson M, Ohlsson T, Knudsen GM, Herth MM, Wellendorph P, Frølund B. Synthesis and Pharmacological Evaluation of [11C]4-Methoxy-N-[2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl]benzamide as a Brain Penetrant PET Ligand Selective for the δ-Subunit-Containing γ-Aminobutyric Acid Type A Receptors. ACS Omega. 2019 May 22;4(5):8846-8851. doi: 10.1021/acsomega.9b00434. PMID: 31459972; PMCID: PMC6648289.
  • Donovan LL, Magnussen JH, Dyssegaard A, Lehel S, Hooker JM, Knudsen GM, Hansen HD. Imaging HDACs In Vivo: Cross-Validation of the [11C]Martinostat Radioligand in the Pig Brain. Mol Imaging Biol. 2020 Jun;22(3):569-577. doi: 10.1007/s11307-019-01403-9. PMID: 31290052.
  • L 'Estrade ET, Shalgunov V, Edgar FG, Strebl-Bantillo MG, Xiong M, Crestey F, Neelamegam R, Dyssegaard A, Lehel S, Erlandsson M, Ohlsson T, Hooker JM, Knudsen GM, Herth MM, Hansen HD. Radiosynthesis and preclinical evaluation of [11 C]Cimbi-701 - Towards the imaging of cerebral 5-HT7 receptors. J Labelled Comp Radiopharm. 2020 Feb;63(2):46-55. doi: 10.1002/jlcr.3808. Epub 2020 Jan 6. PMID: 31674045.