Novel chemically modified analogues of neuropeptide Y for tumor targeting.
The successful use of peptides as potential radiopharmaceuticals essentially requires the modification of the bioactive peptide hormones to introduce chelators for radiolabeling. In this study, four Y 1/Y 2 receptor-selective NPY analogues with different receptor subtype specificities have been investigated. For in vitro studies, the cold metal surrogate was used. Gallium and indium complexes were introduced by using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid as bifunctional chelator. The peptides were synthesized by solid-phase peptide synthesis (SPPS), the chelator was coupled either at the N-terminus or at the N(epsilon) side chain of Lys(4) of the resin-bound peptide, and the labeling was performed in solution after cleavage. Competitive binding assays showed high binding affinity of the receptor-selective analogues at NPY receptor expressing cells. To test internalization of the novel peptide analogues and the metabolic stability in human blood plasma, the corresponding 5(6)-carboxyfluorescein (CF) analogues were prepared and investigated. One of the most promising analogues, the Y 1-receptor selective [Lys(DOTA)(4), Phe(7), Pro(34)]NPY was labeled with (111)In and injected into nude mice that bear MCF-7 breast cancer xenografts, and biodistribution studies were performed. In vitro and in vivo studies suggest that receptor-selective analogues of NPY have promising characteristics for future applications in nuclear medicine for breast tumor diagnosis and therapy.
Institute of Biochemistry, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany.
Denise
D
Zwanziger
Irfan Ullah
IU
Khan
Ines
I
Neundorf
Stephanie
S
Sieger
Lutz
L
Lehmann
Matthias
M
Friebe
Ludger
L
Dinkelborg
Annette G
AG
Beck-Sickinger
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000378:metabolism; D006801:Humans; D007205:Indium Radioisotopes; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D009478:Neuropeptide Y / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D013194:Staining and Labeling; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D008024:Ligands; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid