title: Design, evaluation, and comparison of ghrelin receptor agonists and inverse agonists as suitable radiotracers for PET imaging.
abstract: Ghrelin agonist and inverse agonist radiotracers, suitable for positron emission tomography (PET), were developed to study the behavior of ghrelin receptor ligands in vivo and for further design of druggable peptides. The target peptides were synthesized on solid support and conjugated to the bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which is known to form a stable complex with Ga(3+). Complexation with (68)Ga could be achieved under mild conditions and led to radiotracers with high radiochemical purity and specific activity. The biological activity of the radiotracers was evaluated in vitro by an inositol phosphate turnover assay. Pharmacokinetic profile and metabolic stability of the (68)Ga-NODAGA-radiotracers were investigated by small animal PET in rodent. Ghrelin derived agonists presented very high kidney accumulation, negligible tissue distribution, fast blood clearance, and poor stability in blood. Contrarily, the inverse agonist radiotracer exhibited very high stability in blood, large diffusion in tissues, reasonable kidney and liver metabolism, and slow blood clearance. This pharmacokinetic profile makes the ghrelin inverse agonist motif KwFwLL-CONH(2) suitable for further development of radiotracers and a promising lead to design peptide-based therapeutics against obesity.
authors.affiliation: Institute of Biochemistry, Universität Leipzig, Leipzig, Germany. chollet@rz.uni-leipzig.de
authors.forename: Constance
authors.initials: C
authors.lastname: Chollet
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Annette G
authors.initials: AG
authors.lastname: Beck-Sickinger
mesh_terms: D000085:Acetates / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D054314:Drug Inverse Agonism; D005710:Gallium Radioisotopes; D054439:Ghrelin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D008297:Male; D008969:Molecular Sequence Data; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D051381:Rats; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000819:agonists*
chemical_list: C572723:1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane; D000085:Acetates; D005710:Gallium Radioisotopes; D054439:Ghrelin; D006573:Heterocyclic Compounds, 1-Ring; D011849:Radioactive Tracers; D054440:Receptors, Ghrelin