title: Gallium-67-labeled lactam bridge-cyclized alpha-MSH peptides with enhanced melanoma uptake and reduced renal uptake.
abstract: The purpose of this study was to examine the melanoma targeting and pharmacokinetic properties of (67)Ga-DOTA-GGNle-CycMSHhex {(67)Ga-1,4,7,10-tetraazacyclononane-1,4,7,10-tetraacetic acid-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and (67)Ga-NOTA-GGNle-CycMSHhex {(67)Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and compare with (67)Ga-DOTA-GlyGlu-CycMSH {(67)Ga-DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp]} we previously reported. DOTA-GGNle-CycMSHhex and NOTA-GGNle-CycMSHhex were synthesized using fluorenylmethyloxy carbonyl (Fmoc) chemistry. The melanocortin-1 (MC1) receptor binding affinity of NOTA-GGNle-CycMSHhex was determined in B16/F1 melanoma cells and compared with DOTA-GGNle-CycMSHhex. The melanoma targeting and pharmacokinetic properties of (67)Ga-NOTA-GGNle-CycMSHhex and (67)Ga-DOTA-GGNle-CycMSHhex were determined in B16/F1 melanoma-bearing C57 mice. NOTA-GGNle-CycMSHhex and DOTA-GGNle-CycMSHhex displayed comparable MC1 receptor binding affinities (1.6 vs 2.1 nM) in B16/F1 melanoma cells. Both (67)Ga-NOTA-GGNle-CycMSHhex and (67)Ga-DOTA-GGNle-CycMSHhex exhibited dramatically enhanced melanoma uptake and reduced renal uptake than (67)Ga-DOTA-GlyGlu-CycMSH in B16/F1 melanoma-bearing C57 mice. Furthermore, (67)Ga-NOTA-GGNle-CycMSHhex exhibited more favorable radiolabeling conditions (>85% radiolabeling yields started at 37 °C), as well as higher tumor/kidney uptake ratios than (67)Ga-DOTA-GGNle-CycMSHhex at 0.5, 2, and 24 h postinjection. High melanoma uptake coupled with low renal uptake highlighted the potential of (67)Ga-NOTA-GGNle-CycMSHhex for melanoma imaging and therapy.
authors.affiliation: College of Pharmacy, ‡Cancer Research and Treatment Center, §Department of Dermatology, University of New Mexico , Albuquerque, New Mexico 87131, United States.
authors.forename: Haixun
authors.initials: H
authors.lastname: Guo
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallazzi
authors.forename: Yubin
authors.initials: Y
authors.lastname: Miao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003500:Cyclization; D005260:Female; D005710:Gallium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007769:Lactams / Q000737:chemistry / Q000493:pharmacokinetics*; D008545:Melanoma / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010456:Peptides, Cyclic / Q000737:chemistry / Q000187:drug effects / Q000493:pharmacokinetics*; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D000521:alpha-MSH / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D005710:Gallium Radioisotopes; D007769:Lactams; D010456:Peptides, Cyclic; D044102:Receptor, Melanocortin, Type 1; D000521:alpha-MSH