Reduction of the ring size of radiolabeled lactam bridge-cyclized alpha-MSH peptide, resulting in enhanced melanoma uptake.
The purpose of this study was to examine the profound effect of the ring size of the radiolabeled lactam bridge-cyclized alpha-melanocyte-stimulating hormone (alpha-MSH) peptide on its melanoma-targeting properties.


METHODS
A novel cyclic alpha-MSH peptide, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-CONH(2) (DOTA-Nle-CycMSH(hex)), was synthesized and radiolabeled with (111)In. The melanocortin-1 receptor-binding affinity of DOTA-Nle-CycMSH(hex) was determined in B16/F1 melanoma cells. The internalization and efflux of (111)In-DOTA-Nle-CycMSH(hex) were examined in B16/F1 cells. The melanoma-targeting properties and SPECT/CT characteristics of (111)In-DOTA-Nle-CycMSH(hex) were determined in B16/F1 melanoma-bearing C57 mice.


RESULTS
DOTA-Nle-CycMSH(hex) displayed 1.77 nM receptor-binding affinity. (111)In-DOTA-Nle-CycMSH(hex) exhibited rapid internalization and extended retention in B16/F1 cells. The tumor uptake of (111)In-DOTA-Nle-CycMSH(hex) was 24.94% +/- 4.58% and 10.53% +/- 1.11% injected dose per gram at 0.5 and 24 h after injection, respectively. Greater than 82% of the injected radioactivity was cleared through the urinary system by 2 h after injection. The tumor-to-kidney uptake ratios reached 2.04 and 1.70 at 2 and 4 h after injection, respectively. Flank melanoma tumors were clearly visualized by SPECT/CT using (111)In-DOTA-Nle-CycMSH(hex) as an imaging probe at 2 and 24 h after injection. The radioactivity accumulation in normal organs, except for the kidneys, was low at 2, 4, and 24 h after injection.


CONCLUSIONS
The reduction of the peptide ring size dramatically increased the melanoma uptake and decreased the renal uptake of (111)In-DOTA-Nle-CycMSH(hex), providing a new insight into the design of a novel radiolabeled lactam bridge-cyclized alpha-MSH peptide for melanoma imaging and treatment.
Guo
Haixun
H
College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131, USA.
Yang
Jianquan
J
Gallazzi
Fabio
F
Miao
Yubin
Y
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D003500:Cyclization; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D007205:Indium Radioisotopes / Q000737:chemistry; D007769:Lactams / Q000737:chemistry*; D008545:Melanoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D000521:alpha-MSH / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics
D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D007769:Lactams; D044102:Receptor, Melanocortin, Type 1; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D000521:alpha-MSH