Imaging of melanoma using Cu-64- and Y-86-DOTA-ReCCMSH(Arg(11)), a cyclized peptide analogue of alpha-MSH
Washington University in St. Louis, San Luis, Missouri, United States Journal of Medicinal Chemistry
(Impact Factor: 5.45).
05/2005; 48(8):2985-92. DOI: 10.1021/jm0490282
Early detection of melanoma is essential, since a patient's prognosis with metastatic melanoma is poor. Previous studies showed that (111)In-DOTA-ReCCMSH(Arg(11)), a cyclic analogue of alpha-melanocyte stimulating hormone (alpha-MSH), exhibited high tumor concentration and rapid clearance from nontarget tissue. The goal of this current study was to label DOTA-ReCCMSH(Arg(11)) with beta(+)-emitting radionuclides, to determine if the high sensitivity of positron emission tomography (PET) imaging would aid in the detection of malignant melanoma. DOTA-ReCCMSH(Arg(11)) was labeled with (64)Cu and (86)Y. Biodistribution and small animal PET imaging were carried out in mice implanted with B16/F1 murine melanoma tumor and compared with data obtained in the same animal model with [(18)F]FDG. In both cases a subset of animals were co-injected with 20 microg of DOTA-ReCCMSH(Arg(11)) to determine if tumor concentration was receptor mediated. Tumor concentration for both the (86)Y- and (64)Cu-complexes reached a maximum at 30 min, while coadministering 20 microg of unlabeled complex reduced tumor uptake significantly. Nontarget organ concentration was considerably lower with (86)Y-DOTA-ReCCMSH(Arg(11)) than its (64)Cu analogue, except in the kidneys, where the (64)Cu complex had lower accumulation at all time points. Small animal PET images for both complexes showed the tumor could be visualized after 30 min, with the standardized uptake value (SUV) analysis following a similar trend as the biodistribution data. The data obtained suggests that DOTA-ReCCMSH(Arg(11)), when labeled with beta(+)-emitting radionuclides, has the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of PET.
Available from: Carolyn J Anderson
- "Biodistribution and metabolism studies of 64 Cu-labeled DOTA/TETA monoclonal antibody or peptide conjugates have demonstrated significant dissociation of the 64 Cu from the bifunctional chelator resulting in transchelation to liver superoxide dismutase and other proteins [24,27,42–44]. 64 Cu-labeled DOTA/TETA conjugates often show poor blood and liver clearance, high uptake in some nontarget organs and increased background radioactivity levels, resulting in reduced imaging sensitivity, poor image quality and radiation toxicity  . A series of copper(II) cross-bridged cyclam complexes have been synthesized and characterized, and have demonstrated improved kinetic stability compared with TETA and DOTA complexes  . "
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ABSTRACT: The alpha(v)beta(3) integrin is a cell adhesion molecule known to be involved in stages of angiogenesis and metastasis. In this study, the chelators CB-TE2A and diamsar were conjugated to cyclic RGDyK and RGDfD and the biological properties of (64)Cu-labeled peptides were compared.
CB-TE2A-c(RGDyK) and diamsar-c(RGDfD) were labeled with (64)Cu in 0.1 M NH(4)OAc (pH=8) at 95 degrees C and 25 degrees C, respectively. PET and biodistribution studies were carried out on M21 (alpha(v)beta(3)-positive) and M21L (alpha(v)-negative) melanoma-bearing mice. Binding affinity of the Cu-chelator-RGD peptides to alpha(v)beta(3) integrins was determined by a competitive binding affinity assay.
Biological studies showed higher concentration of (64)Cu-CB-TE2A-c(RGDyK) in M21 tumor compared to M21L tumor at 1 and 4 h pi. Tumor concentration of (64)Cu-CB-TE2A-c(RGDyK) was higher than that of (64)Cu-diamsar-c(RGDfD). The difference is not due to differing binding affinities, since similar values were obtained for the agents. Compared to (64)Cu-diamsar-c(RGDfD), there is more rapid liver and blood clearance of (64)Cu-CB-TE2A-c(RGDyK), resulting in a lower liver and blood concentration at 24 h pi. Both (64)Cu-labeled RGD peptides show similar binding affinities to alpha(v)beta(3). The differences in their biodistribution properties are likely related to different linkers, charges and lipophilicities. The M21 tumor is clearly visualized with (64)Cu-CB-TE2A-c(RGDyK) by microPET imaging. Administration of c(RGDyK) as a block significantly reduced the tumor concentration; however, the radioactivity background was also decreased by the blocking dose.
Both (64)Cu-CB-TE2A-c(RGDyK) and (64)Cu-diamsar-c(RGDfD) are potential candidates for imaging tumor angiogenesis. For diamsar-c(RGDfD), a linker may be needed between the Cu-chelator moiety and the RGD peptide to achieve optimal in vivo tumor concentration and clearance from nontarget organs.
Available from: PubMed Central
- "Currently, the most widely used linear α-MSH peptide analogue is 125I-[Nle4, D-Phe7]-α-MSH, often referred to as a “gold” standard due to its sub-nanomolar receptor binding affinity (Chen et al 2000). Over the last decade, various α-MSH peptides have been radiolabeled with a dazzling number of different radionuclides including 18F (Figure 4) (Cheng et al 2007b; Vaidyanathan and Zalutsky 1997), 99mTc (Chen et al 2002; Chen et al 1999; Giblin et al 1998; Miao et al 2007a), 111In (Bagutti et al 1994; Chen et al 2002; Chen et al 2001; Cheng et al 2002; Froidevaux et al 2005; Froidevaux et al 2002; Miao et al 2007a; Miao et al 2008b; Newton et al 2007), 125I (Chen et al 1999; Cheng et al 2004), 67Ga (Froidevaux et al 2004; Wei et al 2007b), 68Ga (Froidevaux et al 2004; Wei et al 2007b), 86Y (McQuade et al 2005), 64Cu (Cheng et al 2007a; McQuade et al 2005; Wei et al 2007a), 186Re (Giblin et al 1997), 203Pb(Miao et al 2008a), 188Re (Giblin et al 1998; Miao et al 2005c; Miao et al 2003), 90Y (Miao et al 2006; Miao et al 2005a), 177Lu (Miao et al 2006; Miao et al 2005a; Miao et al 2007b), and 212Pb (Miao et al 2005b). Many of these radioisotopes are suitable for imaging only, while several others can also be used for internal radiotherapy applications. "
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ABSTRACT: Skin cancer is the most common form of cancer types. It is generally divided into two categories: melanoma (∼ 5%) and nonmelanoma (∼ 95%), which can be further categorized into basal cell carcinoma, squamous cell carcinoma, and some rare skin cancer types. Biopsy is still the gold standard for skin cancer evaluation in the clinic. Various anatomical imaging techniques have been used to evaluate different types of skin cancer lesions, including laser scanning confocal microscopy, optical coherence tomography, high-frequency ultrasound, terahertz pulsed imaging, magnetic resonance imaging, and some other recently developed techniques such as photoacoustic microscopy. However, anatomical imaging alone may not be sufficient in guiding skin cancer diagnosis and therapy. Over the last decade, various molecular imaging techniques (in particular single photon emission computed tomography and positron emission tomography) have been investigated for skin cancer imaging. The pathways or molecular targets that have been studied include glucose metabolism, integrin α(v)β(3), melanocortin-1 receptor, high molecular weight melanoma-associated antigen, and several other molecular markers. Preclinical molecular imaging is thriving all over the world, while clinical molecular imaging has not lived up to the expectations because of slow bench-to-bedside translation. It is likely that this situation will change in the near future and molecular imaging will truly play an important role in personalized medicine of melanoma patients.
Available from: Andrzej Slominski
- "Radioconjugates of a cyclic peptide analog of α- MSH (eg, coupled with 111 In-DOTA) are being studied as selective agents for early detection of melanoma using positron-emission tomography imaging and as potential therapeutic agents  . The Y86 conjugate appears promising based on high selective uptake in B16 melanoma with rapid clearance from normal tissues . "
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ABSTRACT: The activation or the inhibition of melanocyte-specific receptors offers novel means of augmenting normal melanocyte function, skin color, and photoprotection, or treating melanocytic disorders, namely at this time, metastatic melanoma. Melanocyte-specific receptors include melanocortin-1 (MCR1) and melatonin receptors. Other receptors that play an important role in melanoma progression are G-protein couple receptors such as Frizzled 5 and receptor tyrosine kinases such as c-Kit and hepatocyte growth factor (HGF) receptor. These receptors activate two crucial cell-signaling pathways, RAS/RAF/MEK/ERK and PI3K/AKT, integral to melanoma cell survival, and can serve as targets for therapy of disseminated melanoma. Activation of death receptors is another pathway that can be exploited with targeted therapeutics to control advanced melanoma. This article reviews the current understanding of melanocyte receptors, their agonists and inhibitors, and their potential to treat the melanocytic pathology.
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