title: Synthesis and biological studies of nociceptin derivatives containing the DTPA chelating group for further labeling with therapeutic radionuclides.
abstract: Nociceptin is an endogenous anti-opiate heptadecapeptide primarily interacting with the nociceptin (NOP) receptor. This neuropeptide-receptor system is involved in pain regulation, tolerance to and dependence on opiates as well as many other physiological and pathophysiological events. The role and mechanisms of nociceptin in pathological conditions is not clearly known yet. In an attempt to have a radiopharmaceutical labeled either with 99mTc or (111)In, we incorporated diethylenetriaminepentaacetic acid (DTPA) as chelator into the structure of [Arg14,Lys15]nociceptin(1-17)-NH2 at the epsilon-amino group of Lys15. Such a radiopeptide may be useful in imaging for diagnostical purposes. Preparation of the peptide ligands was carried out by solid phase synthesis. Two peptides containing DTPA were obtained and purified. The products were [Arg14,Lys(DTPA)15]nociceptin(1-17)-NH2 and its cross-linked dimer on the basis of mass spectrometric analysis. In (115)In3+ binding experiments the conjugates exhibited preserved indium ion chelating properties, indicating the potential use of radiolabeled DTPA-nociceptin derivatives as radiopharmaceutical. Biological properties of these compounds were studied in rat brain membrane preparations by radioligand binding, functional biochemical [35S]GTPgammaS binding assays and mouse vas deferens (MVD) bioassay. Besides the similar in vitro binding characteristics to nociceptin receptor, both of the DTPA-chelated compounds were more potent and efficient than nociceptin in functional biochemical and mouse vas deferens bioassays. Our further aim is to radiolabel these compounds in order to get a radiopharmaceutical which can be used diagnostically.
authors.affiliation: Research Group of Peptide Chemistry, Eötvös University and Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Melinda
authors.initials: M
authors.lastname: Ligeti
authors.forename: Ozge
authors.initials: O
authors.lastname: Gündüz
authors.forename: Anna
authors.initials: A
authors.lastname: Magyar
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Kató
authors.forename: András Z
authors.initials: AZ
authors.lastname: Rónai
authors.forename: Claudio
authors.initials: C
authors.lastname: Vita
authors.forename: Imre
authors.initials: I
authors.lastname: Varga
authors.forename: Ferenc
authors.initials: F
authors.lastname: Hudecz
authors.forename: Géza
authors.initials: G
authors.lastname: Tóth
authors.forename: Anna
authors.initials: A
authors.lastname: Borsodi
authors.forename: Sándor
authors.initials: S
authors.lastname: Benyhe
mesh_terms: D000818:Animals; D001681:Biological Assay; D002614:Chelating Agents / Q000737:chemistry*; D019281:Dimerization; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007205:Indium Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004369:Pentetic Acid / Q000737:chemistry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists* / Q000737:chemistry; D013667:Technetium / Q000737:chemistry; D014649:Vas Deferens / Q000187:drug effects; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D002614:Chelating Agents; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007205:Indium Radioisotopes; D018847:Opioid Peptides; D004369:Pentetic Acid; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D011957:Receptors, Opioid; D013667:Technetium; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C504515:nociceptin (1-17)amide, Arg(14)-Lys(DTPA)(15)-