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Melanoma targeting with α-melanocyte stimulating hormone analogs labeled with fac-[99mTc(CO)3]+: effect of cyclization on tumor-seeking properties

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Abstract

Early detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled α-melanocyte stimulating hormone (α-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized α-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of α-MSH (Ac-Nle-cyclo[Asp-His-dPhe-Arg-Trp-Lys]-NH2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of α-MSH analogs by comparing the pharmacokinetics profile of the 99mTc-labeled cyclic peptide βAla-Nle-cyclo[Asp-His-d-Phe-Arg-Trp-Lys]-NH2 with that of the linear analog βAla-Nle-Asp-His-dPhe-Arg-Trp-Lys-NH2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of βAla, and the resulting pz–peptide conjugates were reacted with the fac-[99mTc(CO)3]+ moiety. The 99mTc(CO)3-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic 99mTc(CO)3-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 °C) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 ± 0.83 and 11.31 ± 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear 99mTc(CO)3-pz–peptide presented lower values for both cellular internalization and tumor uptake. Receptor blocking studies with the potent (Nle4,dPhe7)-αMSH agonist demonstrated the specificity of the radioconjugates to MC1R (74.8 and 44.5% reduction of tumor uptake at 4 h after injection for cyclic and linear radioconjugates, respectively).

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Scheme 1
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Abbreviations

αMSH:

α-Melanocyte stimulating hormone

Boc:

tert-Butoxycarbonyl

BSA:

Bovine serum albumin

DMEM:

Dulbecco’s modified Eagle’s medium

DOTA:

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

ESI-MS:

Electrospray ionization mass spectrometry

18F-FDG:

Fluoro-2-deoxyglucose

Fmoc:

9-Fluorenylmethoxycarbonyl

HPLC:

High-performance liquid chromatography

ID:

Injected dose

MC1R:

Melanocortin type 1 receptor

MEM:

Modified Eagle’s medium

MT-II:

Melanotan II

NAPamide:

[Ac–Nle4,Asp5,dPhe7]–αMSH4–11

NDP-MSH:

(Nle4,dPhe7)-αMSH

PBS:

Phosphate-bufered saline

pz:

Tridentate ligand containing a pyrazolyl-diamine backbone

RP:

Reversed phase

TBTU:

O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate

TFA:

Trifluoroacetic acid

TLC:

Thin-layer chromatography

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Acknowledgments

Mallinckrodt-Tyco Inc. is acknowledged for financial support and for providing IsoLink® kits. C.X. thanks Fundação para a Ciência e Tecnologia (FCT) for a PhD grant (SFRH/BD/16680/2004). P.G. thanks FCT for pluriannual funding to the CIQ(UP) research unit.

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Authors and Affiliations

  1. Departamento de Química, ITN, Estrada Nacional 10, 2686-953, Sacavém, Portugal

    Paula D. Raposinho, Catarina Xavier, João D. G. Correia & Isabel Santos

  2. Centro de Investigação em Química da Universidade do Porto, Departamento de Química, Faculdade de Ciências, Universidade do Porto, R. Campo Alegre 687, 4169-007, Porto, Portugal

    Soraia Falcão & Paula Gomes

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  1. Paula D. Raposinho
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  2. Catarina Xavier
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  3. João D. G. Correia
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  5. Paula Gomes
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  6. Isabel Santos
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Correspondence to Isabel Santos.

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Raposinho, P.D., Xavier, C., Correia, J.D.G. et al. Melanoma targeting with α-melanocyte stimulating hormone analogs labeled with fac-[99mTc(CO)3]+: effect of cyclization on tumor-seeking properties. J Biol Inorg Chem 13, 449–459 (2008). https://doi.org/10.1007/s00775-007-0338-3

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