111In-DOTA-Re(Cys3,4,10, d-Phe7,Arg11)αMSH3-13

Excerpt

¹¹¹In-DOTA-[Cys^3,4,10,d-Phe⁷,Arg¹¹]αMSH_3-13 (¹¹¹In-DOTA-Re(Arg¹¹)CCMSH) is a radioligand developed as an imaging probe for single-photon emission computed tomography (SPECT) of primary and metastatic melanoma (1, 2). ¹¹¹In is a gamma emitter with a physical half-life (t_½) of 2.8 days.

Malignant melanoma is the sixth most common cancer in the United States (2). Early diagnosis and prompt surgical removal is the best approach for treatment (2, 3). The melanocortin (MC) system is the best characterized neuropeptide network of the skin, and it is involved in pigmentation regulation, cortisol production, and many other physiological processes (4). Most cutaneous cell types express MC receptors, proopiomelanocortin (POMC), and prohormone convertases, and they also release MCs. Five MC receptors (MC-1 to MC-5) have been cloned and characterized as receptors that belong to the G-protein–coupled receptor superfamily. The melanocyte-stimulating hormones (MSHs) α-, β-, and γ-MSH are derived from POMC by the proteolytic action of prohormone convertases. α-MSH (Ac-Ser¹-Tyr²-Ser³-Met⁴-Glu⁵-His⁶-Phe⁷-Arg⁸-Trp⁹-Gly¹⁰-Lys¹¹-Pro¹²-Val¹³-NH₂), composed of 13 amino acids, is the most potent naturally occurring melanotropic peptide (5). The biologic effects of α-MSH are mediated via MC receptors.

Although positron emission tomography imaging with [¹⁸F]fluoro-2-deoxy-2-d-glucose ([¹⁸F]FDG) is effective in the detection of melanoma, it is not melanoma-specific and some melanoma cells do not take up [¹⁸F]FDG (6, 7). Radiolabeled α-MSH peptide analogs have been shown to specifically bind to MC-1 receptors that are overexpressed on human and mouse melanoma cells (8-11). Giblin et al. (12) used metal cyclization to design a new class of α-MSH peptide analogs that are resistant to chemical and proteolytic degradation in vivo. α-MSH analogs were cyclized through site-specific rhenium (Re) metal coordination to form Re[(Cys^3,4,10,d-Phe⁷)αMSH_3-13 (ReCCMSH). ReCCMSH displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the Re-CMSH analog. Additional studies have reported successful use of 1,4,7,10-tetraazacyclodecane-N,N',N'',N'''-tetraacetic acid (DOTA) coupled to the cyclic ReCCMSH peptide analogs (1, 13) and linear α-MSH analogs (14-16) for radiolabeling. These α-MSH derivatives (DOTA-α-MSH) were labeled with a variety of radionuclides (3, 12, 13, 16-19). Cheng et al. (1) showed that the kidney uptake of a rhenium cyclized DOTA-α-MSH analog [DOTA-Re(Arg¹¹)CCMSH] could be considerably reduced and tumor uptake could be enhanced significantly by substitution the Lys¹¹ residue with Arg¹¹ in order to delocalize the charge of the Lys¹¹ residue. ¹¹¹In-DOTA-Re(Arg¹¹)CCMSH showed favorable tumor imaging properties in mice bearing murine melanoma (2). Miao et al. (11) also replaced the Lys¹¹ with Arg¹¹ in the ReCCMSH analog to form Re(Arg¹¹)CCMSH in an effort to reduce nonspecific kidney uptake and minimize the kidney radiation dose. Linear MSH analogs, conjugated with DOTA, also demonstrated melanoma tumor targeting. Chen et al. (14) demonstrated moderate tumor uptake of the MSH analog ¹¹¹In-DOTA-NDP. Eberle and Froidevaux (15) prepared a minimal α-MSH analog ¹¹¹In-DOTA-MSH_OCT that showed good in vitro and in vivo targeting properties. Froidevaux et al. (16) changed the location of DOTA conjugation to Lys¹¹ yielding DOTA-NAPamide with reduced kidney uptake by neutralizing the charge of the Lys residue. While these linear DOTA-MSH analogs exhibited tumor uptake and rapid clearance, they did not achieve the percent dose per gram and retention time of the cyclic DOTA-MSH peptides.