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Radiolabeled α‐melanocyte‐stimulating hormone analogs for receptor‐mediated targeting of melanoma: from tritium to indium
Author(s) -
Eberle Alex N.,
Froidevaux Sylvie
Publication year - 2003
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.633
Subject(s) - melanocyte stimulating hormone , tritium , chemistry , receptor , melanoma , indium , cancer research , hormone , medicine , endocrinology , biochemistry , organic chemistry , physics , nuclear physics
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 n m ). 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.