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PDBsum entry 2msh
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Hormone/growth factor
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PDB id
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2msh
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References listed in PDB file
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Key reference
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Title
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Design and characterization of alpha-Melanotropin peptide analogs cyclized through rhenium and technetium metal coordination.
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Authors
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M.F.Giblin,
N.Wang,
T.J.Hoffman,
S.S.Jurisson,
T.P.Quinn.
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Ref.
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Proc Natl Acad Sci U S A, 1998,
95,
12814-12818.
[DOI no: ]
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PubMed id
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Abstract
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alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through
site-specific rhenium (Re) and technetium (Tc) metal coordination, were
structurally characterized and analyzed for their abilities to bind alpha-MSH
receptors present on melanoma cells and in tumor-bearing mice. Results from
receptor-binding assays conducted with B16 F1 murine melanoma cells indicated
that receptor-binding affinity was reduced to approximately 1% of its original
levels after Re incorporation into the cyclic Cys4,10, D-Phe7-alpha-MSH4-13
analog. Structural analysis of the Re-peptide complex showed that the disulfide
bond of the original peptide was replaced by thiolate-metal-thiolate
cyclization. A comparison of the metal-bound and metal-free structures indicated
that metal complexation dramatically altered the structure of the
receptor-binding core sequence. Redesign of the metal binding site resulted in a
second-generation Re-peptide complex (ReCCMSH) that displayed a receptor-binding
affinity of 2.9 nM, 25-fold higher than the initial Re-alpha-MSH analog.
Characterization of the second-generation Re-peptide complex indicated that the
peptide was still cyclized through Re coordination, but the structure of the
receptor-binding sequence was no longer constrained. The corresponding 99mTc-
and 188ReCCMSH complexes were synthesized and shown to be stable in
phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic
acid (DTPA) and free cysteine. In vivo, the 99mTcCCMSH complex exhibited
significant tumor uptake and retention and was effective in imaging melanoma in
a murine-tumor model system. Cyclization of alpha-MSH analogs via 99mTc and
188Re yields chemically stable and biologically active molecules with potential
melanoma-imaging and therapeutic properties.
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Figure 1.
Fig. 1. Model structures of APOMSH (Left), ReMSH
(Center), and ReCCMSH (Right) derived from NMR analyses. The
site of Re coordination is depicted by the filled circle in
ReMSH and ReCCMSH molecules.
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Figure 2.
Fig. 2. Imaging of a melanoma tumor in a mouse injected
with 99mTcCCMSH. The  -camera
image of the melanoma-bearing mouse was acquired 30 min
postinjection. The lateral image of the mouse with a 400-mg
tumor shows a high degree of radioactivity localized in the
tumor (b) with lesser amounts present in the kidneys (a),
bladder (c), and tail vein injection site (d). The intensity of
the -emission
is color-coded high-to-low, ranging from white-yellow through
orange, with dark red representing lowest values.
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