title: Introduction of D-phenylalanine enhanced the receptor binding affinities of gonadotropin-releasing hormone peptides.
abstract: The purpose of this study was to examine whether the introduction of D-Phe could improve the GnRH receptor binding affinities of DOTA-conjugated D-Lys(6)-GnRH peptides. Building upon the construct of DOTA-Ahx-(D-Lys(6)-GnRH1) we previously reported, an aromatic amino acid of D-Phe was inserted either between the DOTA and Ahx or between the Ahx and D-Lys(6) to generate new DOTA-D-Phe-Ahx-(D-Lys(6)-GnRH) or DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) peptides. Compared to DOTA-Ahx-(D-Lys(6)-GnRH1) (36.1 nM), the introduction of D-Phe improved the GnRH receptor binding affinities of DOTA-D-Phe-Ahx-(D-Lys(6)-GnRH) (16.3 nM) and DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) (7.6 nM). The tumor targeting and pharmacokinetic properties of (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) was determined in MDA-MB-231 human breast cancer-xenografted nude mice. Compared to (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1), (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) exhibited comparable tumor uptake with faster renal and liver clearance. The MDA-MB-231 human breast cancer-xenografted tumors were clearly visualized by single photon emission computed tomography (SPECT) using (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) as an imaging probe, providing a new insight into the design of new GnRH peptides in the future.
authors.affiliation: College of Pharmacy, University of New Mexico, 2502 Marble NE, MSC09 5360, Albuquerque, NM 87131, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, United States; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, United States.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Hathaway
authors.affiliation: Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, United States; Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, United States.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Royce
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, United States; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, United States.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
authors.affiliation: College of Pharmacy, University of New Mexico, 2502 Marble NE, MSC09 5360, Albuquerque, NM 87131, United States; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, United States; Department of Dermatology, University of New Mexico, Albuquerque, NM 87131, United States. Electronic address: ymiao@salud.unm.edu.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Miao
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000175:diagnosis*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry* / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D061848:Optical Imaging; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011966:Receptors, LHRH / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D010455:Peptides; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D010649:Phenylalanine
keywords: Breast cancer; Gonadotropin-releasing hormone; Receptor binding affinity; SPECT imaging