Potential imaging agents for melanoma based on an active analogue of α-melanocyte-stimulating hormone

Abstract

Both normal and malignant melanocytes possess receptors for the tridecapeptide α-melanocyte-stimulating hormone (MSH). A compound based on this peptide, bisMSH-DTPA (DTPA is diethylenetriamine pentaacetic acid), complexed with indium–111, has been shown to be an effective imaging agent for melanoma in the clinic. BisMSH-DTPA, however, shows unspecific up-take in liver and kidney. In this study, we examine five MSH derivatives, all based on the heptapeptide (Nle⁴, Asp⁵,d-Phe⁷,Lys¹⁰)MSH_(4-10) (MSH_(4-10)). In two of these compounds, monoMSH_(4-10)DTPA and bisMSH_(4-10) DTPA, one or two (MSH_(4-10)) sequences, respectively, were linked to a single molecule of DTPA. The remaining three were designed for iodination, one, MSH_(4-10)BH, was substituted at the N'-terminus with 3-(p-hydroxyphenyl)propionic acid and in the other two, a branched lysyl stucture was constructed at the N'-terminus, which enabled eight tyrosines to be attached. One of these derivatives, MSH_(4-10)Y_sAc, was acetylated but in the other, MSH_(4-10) Y₈, the eight N'-terminal amino groups were left unsubstituted. All of these compounds showed hormonal activity and were capable of targeting isotopes to melanomas in vivo. BisMSH_(4-10) DTPA showed substantially greater tumor uptake than monoMSH_(4-10) DTPA, but slower clearance and more unspecific uptake. Of the iodinated compounds, MSH_(4-10) Y₈ and MSH_(4-10) Y₈Ac showed the greatest tumor uptake, while MSH_(4-10) Y₈ showed substantially less unspecific uptake than MSH_(4-10) Y₈Ac. We conclude that branched lysyl compounds can be used to deliver multiple targeted moieties to each receptor and that unspecific uptake can be controlled by reducing hydrophobicity.