|dc.description.abstract||The overall aim of the thesis was to evaluate the potential of gonadotropin releasing hormone receptor (GnRH-R) antagonists as radiotracers for the early detection and understanding of Alzheimer`s disease (AD). The molecular imaging field is a symbiosis between organic chemistry, radiochemistry, in vitro biology, as well as preclinical- and clinical trials, therefore an evaluation should involve all respective subfields. In light of this, the development of a new radiotracer is often a time- consuming and laborious process. Consequently, this thesis represents a highly collaborative project involving various subfields and their interplay in the field of molecular imaging.
Initially a series of GnRH-R antagonists were synthesized and evaluated for affinity for the GnRH-receptor. A competitive binding study was performed and the synthesized GnRH-R antagonists were compared to control compounds. By the use of a copper mediated late-stage iodination, radiolabeling was further investigated. In addition, an acylation Finkelstein approach was examined by a thorough mechanistic analysis using both experimental and computational methods. The in vitro analyses of two promising GnRH-R antagonists were performed, where human and rat serum stability, a competitive inhibition assay, a metabolic profile (phase 1) and autoradiography evaluated the potential these compounds exhibit as radiotracers. Furthermore, preclinical evaluation of a α-halogenated compound was performed on the basis of literature findings and serum stability analysis.
In summary, the project has resulted in several potential GnRH-R antagonist radiotracers. Although more analyses need to be performed, one compound has already been evaluated in preclinical trials and excluded from further investigation. Two more compounds have been radiolabeled and assessed thoroughly in vitro. The compounds showed good affinity for the GnRH-R. Serum stability analysis and the metabolic profiling showed stable compounds for imaging. In addition, several metabolites were identified and the metabolic rate was quantified. Furthermore, autoradiography in rat brain showed binding, which was in compliance with binding affinities for the compound. These new GnRH-R antagonists possess high potential as GnRH- antagonistic radiotracers for the pathophysiologic examination of AD and warrant further preclinical evaluation.||en_US
|dc.relation.haspart||Paper I: Fjellaksel, R., Boomgaren, M., Sundset, R., Haraldsen, I.H., Hansen, J.H. & Riss, P. (2017). Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor. <i>MedChemComm, 8</i>(10), 1965-1969. Also available at <a href=https://doi.org/10.1039/C7MD00320J>https://doi.org/10.1039/C7MD00320J. </a><p>
<p>Paper II: Fjellaksel, R., Sundset, R., Riss, P.J. & Hansen, J.H. (2018). Copper-mediated late-stage iodination and <sup>123</sup>I-labelling of triazole-benzimidazole bioactives. <i>Synlett, 29</i>(11), 1491-1495. The paper is not available in Munin due to publisher restrictions. Available at <a href=https://doi.org/10.1055/s-0036-1591985> https://doi.org/10.1055/s-0036-1591985. </a><p>
<p>Paper III: Fjellaksel, R., Dugalic, D., Demissie, T.B., Riss, P.J., Hjelstuen, O-K., Sundset, R. & Hansen, J.H. (2018). An Acylation-Finkelstein Approach to Radioiodination of Bioactives: The role of amide group anchimeric assistance. <i>Journal of Physical Organic Chemistry, 31</i>(7), e3835. Also available at <a href= https://doi.org/10.1002/poc.3835> https://doi.org/10.1002/poc.3835</a>. Accepted manuscript available in Munin at <a href= https://hdl.handle.net/10037/13421> https://hdl.handle.net/10037/13421. </a><p>
<p>Paper IV: Fjellaksel, R., Moldes-Anaya, A., Oteiza, A., Martin-Armas, M., Vasskog, T., Riss, P.J. & Sundset, R. In vitro evaluation of two promising bioactive triazole-benzimidazole GnRH Receptor-antagonists as possible candidates for SPECT imaging. (Manuscript). Final version with altered title is available in Munin at <a href=https://hdl.handle.net/10037/17184>https://hdl.handle.net/10037/17184. </a><p>
<p>Paper V: Fjellaksel, R., Oteiza, A., Martin-Armas, M., Riss, P.J., Hjelstuen, O.K., Kuttner, S. … Sundset, R. First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor based upon the piperazinylbenzimidazole class of compounds. (Manuscript). Final version available in Munin at <a href= https://hdl.handle.net/10037/14656> https://hdl.handle.net/10037/14656. </a><p>||en_US