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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis of Neuropeptide Y Analogues as PET Imaging AgentsSimon J. Mountford 1 , Lei Zhang 2 , Herbert Herzog 2 , Bim Graham 1 ,and Philip E. Thompson 11 Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences,Parkville, VIC, 3052, Australia; 2 Neuroscience Research Program, Garvan Institute ofMedical Research, St Vincent's Hospital, Darlinghurst, NSW, 2010IntroductionNeuropeptide Y is a 36-amino acid peptide that belongs to a family of structurally relatedpeptides including pancreatic polypeptide (PP) and peptide YY (PYY). NPY is a peptideneurotransmitter mediating effects at the central nervous system [1] (e.g. stimulation offeeding behaviour and inhibition of anxiety) and the peripheral nervous system [2] (e.g.vasoconstriction, insulin release, renal secretion, gastrointestinal secretion). These centraland peripheral activities are mediated by at least six G-protein coupled receptor subtypes(Y1, Y2, Y3, Y4, Y5, and y6) [3]. Over-expression of receptor subtype Y1 occurs in humantumours such as breast cancer [4] and therefore selective Y1-receptor peptide conjugateswith the appropriate pharmacokinetic properties may be suitable for imaging and/ordelivery of radiotherapy. However, the inclusion of auxiliary imaging groups on to peptidescan dramatically change the potency and selectivity of the resultant conjugate.Incorporation of labels must not compromise the molecular recognition of the ligand by thereceptor and retain the selectivity for the Y1-receptor. We are pursuing analogues of avariety of Y1 ligands, including novel amino acids whereby the side chain is modified toallow attachment of radiolabels or other imaging agents via click chemistry. In this paperwe report on the synthetic approaches to such compounds.Results and DiscussionWe have developed syntheses of three reported Y1 ligands, [5,6] that can be adapted forinclusion of imaging agents. Included among these, are efficient synthesis of the cyclicdisulfide-bridged peptide 1, (Figure 1), and the cyclic lactam bridged dimer, GR231118, 2.Peptides were synthesized using Fmoc-based solid phase peptide synthesis on a ProteinTechnologies PS3, automated peptide synthesizer on Rink Amide resin (0.7 meq).Couplings were performed using 3-fold excess of Fmoc-protected amino acid andHCTU/DIPEA for activation. After cleavage (Reagent K, 2h) peptides were purified byRP-HPLC. Oxidation to produce 1 was performed with 25mM NH 4 HCO 3 (aq), 18h at RT.Synthesis of the dimeric peptide, 2, was achieved by treatment of the Fmoc-protected linearprecursor Ile-Glu-Pro-Dap-Tyr-Arg-Leu-Arg-Tyr-NH 2 , with PyBOP at RT followed byFmoc-deprotection with piperidine/DMF.Fig. 1. HPLC trace of disulfide bridged peptide 1, spiked with linear precursor. ESI-MSof purified product.212