Metastatic melanoma imaging with an 111In-labeled lactam bridge-cyclized α-melanocyte-stimulating hormone peptide

doi:10.1016/j.nucmedbio.2009.01.003

Nuclear Medicine and Biology

Volume 36, Issue 3, April 2009, Pages 267-276

https://doi.org/10.1016/j.nucmedbio.2009.01.003 Get rights and content

Abstract

Introduction

The purpose of this study was to examine whether a novel lactam bridge-cyclized ¹¹¹In-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Gly-Glu-c[Lys-Nle-Glu-His-d-Phe-Arg-Trp-Gly-Arg-Pro-Val-Asp] {DOTA-GlyGlu-CycMSH} could be an effective imaging probe for metastatic melanoma detection.

Methods

¹¹¹In-DOTA-GlyGlu-CycMSH was prepared and purified by reverse-phase high-performance liquid chromatography (RP-HPLC). The internalization and efflux of ¹¹¹In-DOTA-GlyGlu-CycMSH were examined in B16/F10 melanoma cells. The biodistribution of ¹¹¹In-DOTA-GlyGlu-CycMSH was determined in B16/F10 pulmonary metastatic melanoma-bearing and normal C57 mice. Pulmonary metastatic melanoma imaging was performed by small-animal single-photon emission computed tomography (SPECT)/CT (Nano-SPECT/CT) using ¹¹¹In-DOTA-GlyGlu-CycMSH as an imaging probe and compared with 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) positron emission tomography (PET) imaging.

Results

¹¹¹In-DOTA-GlyGlu-CycMSH was readily prepared with greater than 95% radiolabeling yield. ¹¹¹In-DOTA-GlyGlu-CycMSH displayed rapid internalization and extended efflux in B16/F10 cells. ¹¹¹In-DOTA-GlyGlu-CycMSH exhibited significantly (P<.05) higher uptakes (2.00±0.74%ID/g at 2 h post-injection and 1.83±0.12%ID/g at 4 h post-injection) in metastatic melanoma-bearing lung than that in normal lung (0.08±0.08%ID/g and 0.05±0.05%ID/g at 2 and 4 h post-injection, respectively). The activity accumulation in normal organs was low (<0.5%ID/g) except for the kidneys 2 and 4 h post-injection. B16/F10 pulmonary melanoma metastases were clearly visualized with ¹¹¹In-DOTA-GlyGlu-CycMSH 2 h post-injection rather than with [¹⁸F]FDG 1 h post-injection.

Conclusions

¹¹¹In-DOTA-GlyGlu-CycMSH exhibited favorable metastatic melanoma-targeting and -imaging properties, highlighting its potential as an effective imaging probe for metastatic melanoma detection.

Introduction

Skin cancer is the most commonly diagnosed cancer in the United States. Malignant melanoma is the most lethal form of skin cancer and the most commonly diagnosed malignancy among young adults with an increasing incidence. It was predicted that there would be 62,940 cases of malignant melanoma newly reported and 8420 fatalities in 2008 [1]. Melanoma metastases are highly aggressive, and the survival time for patients with metastatic melanoma averages 3–15 months [2]. Unfortunately, no curative treatment exists for metastatic melanoma. Early diagnosis and prompt surgical removal are a patient's best opportunity for a cure. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques are attractive, noninvasive imaging modalities due to their high sensitivity (10⁻¹⁰ to 10⁻¹¹ M for SPECT and 10⁻¹¹ to 10⁻¹² M for PET) and spatial resolution (1–2 mm) [3], [4]. Currently, 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) PET imaging is commonly used for the diagnosis and staging of melanoma. However, [¹⁸F]FDG is not a melanoma-specific imaging probe since the elevated uptake of [¹⁸F]FDG in tumor is due to the higher metabolism and energy consumption in tumor cells than that in normal cells. [¹⁸F]FDG PET imaging only detects 23% melanoma metastases smaller than 5 mm [5]. Meanwhile, some melanoma cells are not detected by [¹⁸F]FDG PET imaging since they use substrates other than glucose as energy sources [6], [7]. Therefore, it is highly desirable to develop novel effective imaging probes to detect primary, metastatic, and recurrent melanomas.

G-protein-coupled melanocortin-1 (MC1) receptors have been used as targets to develop melanoma-specific imaging probes due to their overexpression on human and mouse melanoma cells [8], [9], [10], [11], [12]. Radiolabeled α-melanocyte-stimulating hormone (α-MSH) peptide analogues, derived from wild-type α-MSH, are very promising candidates for melanoma imaging and therapy due to their nanomolar MC1 receptor binding affinities and high receptor-mediated tumor uptakes in murine melanoma-bearing mice and human melanoma xenografts [13], [14], [15], [16], [17]. Novel ¹¹¹In-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated lactam bridge-cyclized α-MSH peptides were developed to target MC1 receptors for melanoma imaging in our previous report [18]. Lactam bridge cyclization was employed to improve the stabilities of the peptides against the proteolytic degradations in vivo and enhance the binding affinities of the peptides through stabilizing their secondary structures such as β turns [19], [20], [21], [22]. DOTA was coupled to the lactam bridge-cyclized peptides directly or through a negatively charged amino acid linker (-Gly-Glu-) to determine the effect of a negatively charged linker in reducing the renal uptakes of ¹¹¹In-labeled lactam bridge-cyclized peptides. Introduction of a negatively charged amino acid linker (-Gly-Glu-) into the peptide sequence decreased the renal uptakes by 44% without affecting the tumor uptakes 4 h post-injection. ¹¹¹In-labeled DOTA-GlyGlu-CycMSH (DOTA-Gly-Glu-c[Lys-Nle-Glu-His-d-Phe-Arg-Trp-Gly-Arg-Pro-Val-Asp]) exhibited high receptor-mediated tumor uptake (10.40±1.40%ID/g at 2 h post-injection) in the flank B16/F1 murine melanoma-bearing mouse model [18], highlighting the potential of using ¹¹¹In-labeled DOTA-GlyGlu-CycMSH as a melanoma-specific imaging probe for metastatic melanoma detection.

In this study, ¹¹¹In-labeled DOTA-GlyGlu-CycMSH was further evaluated in B16/F10 pulmonary metastatic melanoma mouse model to validate its feasibility as an effective melanoma-specific imaging probe for melanoma metastases detection. The biodistribution of ¹¹¹In-labeled DOTA-GlyGlu-CycMSH was determined in the B16/F10 pulmonary metastatic melanoma-bearing C57 mice and compared with that in the normal C57 mice. Dual-modality small-animal SPECT/CT (Nano-SPECT/CT) was used to detect different-stage pulmonary melanoma metastases using ¹¹¹In-labeled DOTA-GlyGlu-CycMSH as an imaging probe to monitor the development of melanoma metastases. The imaging properties on melanoma metastases between [¹⁸F]FDG PET imaging and ¹¹¹In-DOTA-GlyGlu-CycMSH SPECT/CT imaging were compared by injecting [¹⁸F]FDG and ¹¹¹In-DOTA-GlyGlu-CycMSH with a time interval of 26 h in a pulmonary metastatic melanoma-bearing mouse, respectively.

Section snippets

Chemicals and reagents

Amino acid and resin were purchased from Advanced ChemTech Inc. (Louisville, KY) and Novabiochem (San Diego, CA). DOTA-tri-t-butyl ester was purchased from Macrocyclics Inc. (Richardson, TX). ¹¹¹InCl₃ was purchased from Trace Life Sciences, Inc. (Dallas, TX). ¹²⁵I-Tyr²-[Nle⁴, d-Phe⁷]-α-MSH {¹²⁵I-(Tyr²)-NDP-MSH} was obtained from PerkinElmer, Inc. (Shelton, CT). All other chemicals used in this study were purchased from Thermo Fisher Scientific (Waltham, MA) and used without further

Results

The MC1 receptor density of the B16/F10 cell was determined by saturation binding assay using commercial ¹²⁵I-(Tyr²)-NDP-MSH as a radioactive tracer. The saturation curve and Scatchard plot are presented in Fig. 1. The B_max of B16/F10 cells was 23,394 dpm/million cells (2884 receptors/cell). DOTA-GlyGlu-CycMSH was synthesized, purified by RP-HPLC and identified by electrospray ionization mass spectrometry. Fig. 2 illustrates the competitive binding curve of DOTA-GlyGlu-CycMSH in B16/F10 cells.

Discussion

High mortality of malignant melanoma is associated with the occurrence of metastatic melanoma due to its aggressiveness and resistance to current chemotherapy and immunotherapy regimens. Early diagnosis and prompt surgical removal of the malignant melanoma provide the patients the best opportunities for cures or prolonged survival. Despite the clinical use of [¹⁸F]FDG in melanoma staging and melanoma metastases identification, [¹⁸F]FDG is not a melanoma-specific imaging agent and is also not

Acknowledgments

This work was supported in part by the University of New Mexico—Los Alamos National Laboratory MOU on Research and Education Grant 2R76T, the American Foundation for Pharmaceutical Education Grant 3R48E, the American Cancer Society Institutional Research Grant IRG-92-024, New Mexico Technology Research Collaborative Grant 3R44N, the University of New Mexico Cancer Research and Treatment Center (NIH P30 CA118100), the Stranahan Foundation and the W.M. Keck Foundation. We thank Drs. Scott W.

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The purpose of this study was to evaluate the effect of cyclization on the biological profile of a [^99mTc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analog. A lactam bridge-cyclized H-Cys-Ahx-βAla³-c[Lys⁴-Glu-His-D-Phe-Arg-Trp-Glu¹⁰]-Arg¹¹-Pro-Val-NH₂ (NAP―NS2) and the corresponding linear H-Cys-Ahx-βAla-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH₂ (NAP―NS1) peptide were synthetized, characterized by ESI-MS spectroscopy and their melanocortin-1 receptor (MC1R) binding affinity was determined in B16/F10 melanoma cells. The consistent [^99mTc(N)(PNP3)]-labeled compounds were readily obtained in high specific activity and their stability and biological properties were assessed. As an example, the chemical identity of [^99mTc(N)(NAP–NS1)(PNP3)]⁺ was confirmed by carrier added experiments supported by radio/UV HPLC analysis combined with ESI(+)-MS.
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Metastatic melanoma imaging with an 111In-labeled lactam bridge-cyclized α-melanocyte-stimulating hormone peptide

Abstract

Introduction

Methods

Results

Conclusions

Introduction

Section snippets

Chemicals and reagents

Results

Discussion

Acknowledgments

Curr Opin Chem Biol

Lancet Oncol

Lancet

Cancer statistics, 2008

CA Cancer J Clin

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system

J Clin Oncol

Molecular imaging of cancer with positron emission tomography

Nat Rev Cancer

Molecular imaging of gene expression and protein function in vivo with PET and SPECT

J Magn Reson Imaging

Staging of regional lymph nodes in melanoma patients by means of 99mTc-MIBI scintigraphy

J Nucl Med

Clinical application of 18F-FDG in oncology

J Nucl Med Technol

Quantitative PET studies in pretreated melanoma patients: a comparison of 6-[18F]fluoro-l-DOPA with 18F-FDG and 15O-water using compartment and non-compartment analysis

J Nucl Med

Specific receptors for alpha-melanocyte-stimulating hormone are widely distributed in tissues of rodents

Endocrinology

Characterization of receptors for alpha-melanocyte-stimulating hormone on human melanoma cells

Cancer Res

Melanoma-targeting properties of 99mtechnetium-labeled cyclic α-melanocyte-stimulating hormone peptide analogues

Cancer Res

In vivo evaluation of 188Re-labeled alpha-melanocyte stimulating hormone peptide analogs for melanoma therapy

Int J Cancer

Evaluation of the human melanoma targeting properties of radiolabeled alpha-melanocyte stimulating hormone peptide analogues

Bioconjug Chem

Therapeutic efficacy of a 188Re labeled α-melanocyte stimulating hormone peptide analogue in murine and human melanoma-bearing mouse models

J Nucl Med

Melanoma therapy via peptide-targeted α-radiation

Clin Cancer Res

A novel DOTA-α-melanocyte-stimulating hormone analog for metastatic melanoma diagnosis

J Nucl Med

Metastatic melanoma imaging with an ¹¹¹In-labeled lactam bridge-cyclized α-melanocyte-stimulating hormone peptide

Staging of regional lymph nodes in melanoma patients by means of ^99mTc-MIBI scintigraphy

Clinical application of ¹⁸F-FDG in oncology

Quantitative PET studies in pretreated melanoma patients: a comparison of 6-[¹⁸F]fluoro-l-DOPA with ¹⁸F-FDG and ¹⁵O-water using compartment and non-compartment analysis

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