Evaluation by metabolic profiling and in vitro autoradiography of two promising GnRH‐receptor ligands for brain SPECT imaging
| Autor: | Angel Moldes-Anaya, Terje Vasskog, Ana Oteiza, Ole Kristian Hjelstuen, Maria Montserrat Martin-Armas, Richard Fjellaksel, Patrick J. Riss, Rune Sundset, Jørn H. Hansen |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.drug_class
Ligands 01 natural sciences Biochemistry 030218 nuclear medicine & medical imaging Analytical Chemistry 03 medical and health sciences 0302 clinical medicine Spect imaging Drug Discovery medicine Animals Humans Metabolomics Radiology Nuclear Medicine and imaging Receptor Spectroscopy Tomography Emission-Computed Single-Photon 010405 organic chemistry Chemistry Organic Chemistry Brain VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 Metabolism medicine.disease VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 In vitro 0104 chemical sciences Rats Microsome Autoradiography Alzheimer's disease Gonadotropin Gonadotropin-releasing hormone receptor Receptors LHRH |
| ISSN: | 0362-4803 |
| Popis: | The increased expression of gonadotropin releasing hormone receptor (GnRH‐R) in brain has been strongly linked to Alzheimer disease. Therefore, the development of radiolabeled imaging agents for GnRH‐R is relevant for early diagnosis of Alzheimer disease. We have recently disclosed the discovery of two promising compounds displaying nanomolar‐range affinity for the GnRH‐R. In the present study, a preclinical evaluation of the compound properties was performed to evaluate their potential as single photon emission computed tomography (SPECT) radiotracers for imaging the GnRH‐receptor. The compounds were assessed in vitro by performing serum stability analysis by human and rat serum, metabolic profiling by human liver microsomes, and exploratory rat brain autoradiography. The investigated compounds displayed satisfactory stability against human, rat serum, and liver microsomal metabolism, which favors their potential as SPECT‐imaging agents. Additionally, we identified and quantified the formation rate of the metabolites by fragmentation of up to five mass spectrometric stages. The GnRH‐R rat brain specificity of these compounds was tested in competition with a known ligand for the receptor and the in vitro autoradiography confirmed that compounds 3 and 4 binds to rat GnRH‐R in different rat brain regions. |
| Databáze: | OpenAIRE |
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