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Modification of the Structure of a Metallopeptide:  Synthesis and Biological Evaluation of 111In-Labeled DOTA-Conjugated Rhenium-Cyclized α-MSH Analogues

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Departments of Chemistry, 125 Chemistry Building, and Biochemistry, 117 Schweitzer Hall, University of Missouri-Columbia, and Harry S. Truman Memorial Veteran's Hospital, Columbia, Missouri 65211
Cite this: J. Med. Chem. 2002, 45, 14, 3048–3056
Publication Date (Web):June 4, 2002
Copyright © 2002 American Chemical Society

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    Abstract Image

    Rhenium-cyclized CCMSH analogues are novel melanoma-targeting metallopeptides with high tumor uptake, long tumor retention, and low background in normal tissues, which make these metallopeptides an ideal structural motif for designing novel melanoma-targeting agents. ReCCMSH has been derivatized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate so that it can be labeled with a wide variety of radionuclides for imaging and therapeutic applications. This study involved optimization of the in vivo biological properties of DOTA-ReCCMSH (S), through modification of the structure of the metallopeptide. Several DOTA-ReCCMSH analogues, Ac-Lys(DOTA)-ReCCMSH (4) DOTA-ReCCMSH(Arg11) (6), DOTA-ReCCMSH-OH (8), and DOTA-ReCCMSH-Asp-OH (10), were synthesized using solid phase peptide synthesis followed by rhenium cyclization. The IC50 values of the metallopeptides were determined through competitive binding assays against 125I-(Tyr2)-NDP. Radiolabeling of the DOTA-rhenium-cyclized peptides with 111In was carried out in NH4OAc (0.1 M; pH 5.5)-buffered solution for 30 min at 70 °C. The stability of the radiolabeled complexes was evaluated in 0.01 M, pH 7.4, phosphate-buffered saline/0.1% bovine serum albumin solution. After separation of the radiolabeled peptide from the unlabeled peptide by reverse phase high-performance liquid chromatography, the biodistribution of the radiolabeled complex was performed in C57 mice bearing B16/F1 murine melanoma tumors. All radiolabeled complexes showed fast blood clearance (2 h postinjection (pi):  111In-S, 0.07 ± 0.03% ID/g; 111In-4, 0.09 ± 0.06% ID/g; 111In-6, 0.21 ± 0.08% ID/g; 111In-8, 0.11 ± 0.10% ID/g; and 111In-10, 0.05 ± 0.03% ID/g), and their clearance was predominantly through the urine (4 h pi:  93.5 ± 1.7, 87.8 ± 6.5, 89.8 ± 4.2, 93.3 ± 1.1, and 93.8 ± 1.8 (% ID) for 111In-labeled S, 4, 6, 8, and 10, respectively). Tumor uptake values of 9.45 ± 0.90, 6.01 ± 2.36, 17.41 ± 5.61, 9.27 ± 0.68, and 7.32 ± 2.09 (% ID/g) for 111In-labeled S, 4, 6, 8, and 10, respectively, were observed at 4 h pi. The kidney uptake was 9.27 ± 2.65% ID/g for 111In-S, 19.02 ± 2.63% ID/g for 111In-4, 7.37 ± 1.13% ID/g for 111In-6, 8.70 ± 0.88% ID/g for 111In-8, and 8.13 ± 1.47% ID/g for 111In-10 at 4 h pi. Complex 6 showed high melanoma uptake and lower kidney uptake than the corresponding Lys11 analogues, supporting 6 for further investigations as a potential therapeutic radiopharmaceutical.

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     Department of Chemistry, University of Missouri-Columbia.

     Department of Biochemistry, University of Missouri-Columbia.


     Harry S. Truman Memorial Veteran's Hospital.


     To whom correspondence should be addressed. T.P.Q.:  Tel.:  573-882-6099. Fax:  573-884-4812. E-mail:  [email protected]. S.S.J.:  Tel.: 573-882-2107. Fax: 573-882-2754. E-mail: [email protected].

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