Abstract
Following the first synthesis of tritiated α‐melanocyte‐stimulating hormone (α‐MSH, α‐melanotropin) in 1974 by Medzihradszky et al., several α‐MSH analogs were designed containing between 2 and 12 tritium atoms, the latter of which displayed a specific radioactivity of 12.21 GBq/μmol (330 Ci/mmol). Similarly, radioiodinated α‐MSH analogs of high purity, full biological activity and a specific radioactivity of approximatly 140 GBq/μmol were obtained. Although tritiated and radioiodinated α‐MSH became indispensable tools as tracer molecules for numerous in vitro and in vivo studies, above all for receptor identification and characterization as well as for structure‐activity studies, they did not fulfill the criteria required for therapeutic in vivo targeting of metastatic melanoma. Therefore, we recently developed α‐MSH analogs containing the universal metal chelator 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) in different positions of the molecule. As DOTA can equally well incorporate diagnostic (e.g. ^111^In, ^67,68^Ga) and therapeutic (e.g. ^90^Y, ^67^Cu) radionuclides, DOTA‐MSH compounds may serve for both melanoma scintigraphy and therapy. The analog DOTA‐[βAla^3^, Nle^4^, Asp^5^, D‐Phe^7^, Lys^10^]‐α‐MSH~3–10~ (DOTA‐MSH~OCT~), which contains the metal chelator at its N‐terminal end, displayed good in vitro MC1R affinity (IC~50~ 9.21 nm). In vivo, [^111^In]DOTA‐MSH~OCT~ exhibited a favorable biodistribution profile after injection in B16‐F1 tumor‐bearing mice. The radiopeptide was rapidly cleared from blood through the kidneys and, most importantly, accumulated preferentially in the melanoma lesions. Lung and liver melanoma metastases could be clearly imaged on tissue section autoradiographs 4 h after injection of [^111^In]DOTA‐MSH~OCT~. A comparative study of [^111^In]DOTA‐MSH~OCT~ with [^111^In]DOTA‐[Nle^4^, D‐Phe^7^]‐α‐MSH ([^111^In]DOTA‐NDP‐MSH) demonstrated the superiority of the DOTA‐MSH~OCT~ peptide, particularly with respect to the amount of radioactivity taken up by non‐malignant organs, including bone, the most radiosensitive tissue. These results demonstrate that [^111^In]DOTA‐MSH~OCT~ specifically targets melanoma metastases and represents a lead compound for the development of therapeutic DOTA‐MSH analogs. Copyright © 2003 John Wiley & Sons, Ltd.