Brain penetrant small 18F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats

Olberg, Dag E., Bauer, Nadine, Andressen, Kjetil W., Hjørnevik, Trine, Cumming, Paul, Levy, Finn O., Klaveness, Jo, Haraldsen, Ira, & Sutcliffe, Julie L. (2016) Brain penetrant small 18F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats. Nuclear Medicine and Biology, 43(8), pp. 478-489.

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The gonadotropin releasing hormone receptor (GnRH-R) has a well-described neuroendocrine function in the anterior pituitary. However, little is known about its function in the central nervous system (CNS), where it is most abundantly expressed in hippocampus and amygdala. Since peptide ligands based upon the endogenous decapetide GnRH do not pass the blood brain-barrier, we are seeking a high-affinity small molecule GnRH-R ligand suitable for brain imaging by positron emission tomography. We have previously reported the radiosynthesis and in vitro evaluation of two novel [18F]fluorinated GnRH-R ligands belonging to the furamide class of antagonists, with molecular weight less than 500 Da. We now extend this work using palladium coupling for the synthesis of four novel radioligands, with putatively reduced polar surface area and hydrophilicity relative to the two previously described compounds, and report the uptake of these 18F-labeled compounds in brain of living rats.


We synthesized reference standards of the small molecule GnRH-R antagonists as well as mesylate precursors for 18F-labeling. The antagonists were tested for binding affinity for both human and rat GnRH-R. Serum and blood stability in vitro and in vivo were studied. Biodistribution and PET imaging studies were performed in male rats in order to assess brain penetration in vivo.


A palladium coupling methodology served for the synthesis of four novel fluorinated furamide GnRH receptor antagonists with reduced heteroatomic count. Radioligand binding assays in vitro revealed subnanomolar affinity of the new fluorinated compounds for both human and rat GnRH-R. The 18F-GnRH antagonists were synthesized from the corresponding mesylate precursors in 5-15% overall radiochemical yield. The radiolabeled compounds demonstrated good in vivo stability. PET imaging with the 18F-radiotracers in naive rats showed good permeability into brain and rapid washout, but absence of discernible specific binding in vivo.


The novel small molecule 18F-fluorinated GnRH-R antagonist compounds show high receptor affinity in vitro, and may prove useful for quantitative autoradiographic studies in vitro. The compounds were permeable to the blood-brain barrier, but nonetheless failed to reveal significant specific binding in brain of living rats. Nonetheless, our approach may serve as a foundation for designing PET ligands suitable to image the GnRH-R distribution in brain.

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1 citations in Web of Science®
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ID Code: 99721
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: positron emission tomography, GnRH receptor, brain imaging, Buchwald-Hartwig, GnRH-R furamide antagonists
DOI: 10.1016/j.nucmedbio.2016.05.003
ISSN: 1872-9614
Subjects: Australian and New Zealand Standard Research Classification > PSYCHOLOGY AND COGNITIVE SCIENCES (170000) > PSYCHOLOGY (170100) > Biological Psychology (Neuropsychology Psychopharmacology Physiological Psychology) (170101)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Current > Schools > School of Psychology & Counselling
Deposited On: 13 Oct 2016 00:48
Last Modified: 13 Oct 2016 21:43

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