title: Preclinical Melanoma Imaging with68Ga-Labeled α-Melanocyte-Stimulating Hormone Derivatives Using PET.
abstract: It is estimated that melanoma accounted for 76,380 new cases and 10,130 deaths in the United States in 2016. The melanocortin 1 receptor (MC1R) is highly expressed in the vast majority of melanomas, which makes it an attractive target for molecular imaging and radionuclide therapy. Lactam bridge-cyclized α-melanocyte-stimulating hormone (Ac-Nle4-cyclo[Asp5-His-D-Phe7-Arg-Trp-Lys10]-NH2, or Nle-CycMSHhex) analogues have been successfully developed and studied for MC1R-targeted imaging, predominantly with single-photon emission computed tomography (SPECT). The goal of this study was to design and evaluate novel peptides for melanoma imaging with positron emission tomography (PET). We designed and synthesized three peptides, DOTA-PEG2-Nle-CycMSHhex(CCZ01047), DOTA-4-amino-(1-carboxymethyl) piperidine (Pip)-Nle-CycMSHhex(CCZ01048), and DOTA-Pip-Pip-Nle-CycMSHhex(CCZ01056). All three peptides exhibited high binding affinity to MC1R with sub-nanomolar Kivalues, rapid internalization into B16F10 melanoma cells and highin vivostability with more than 93% remaining intact at 15 min post-injection (p.i.) in blood plasma. All three68Ga-labeled tracers produced high contrast PET images in C57BL/6J mice bearing B16F10 tumors, and their respective tumor uptakes were 8.0 ± 3.0, 12.3 ± 3.3, and 6.5 ± 1.4 %ID/g at 1 h p.i. Minimal normal organ activity was observed at 1 h p.i., except for kidneys (5.1 ± 1.4, 4.7 ± 0.5, and 6.2 ± 2.0 %ID/g, respectively), and thyroid (4.1 ± 0.6 %ID/g for CCZ01047 and 2.4 ± 0.6 %ID/g for CCZ01048). Due to high accumulation at tumor sites and rapid background clearance of68Ga-CCZ01048, we further evaluated it at 2 h p.i., and a tumor uptake of 21.9 ± 4.6 %ID/g was observed, with background activity further decreased. Exceptional image contrast was also achieved, i.e. tumor-to-blood, tumor-to-muscle, tumor-to-bone and tumor-to-kidney ratios were 96.4 ± 13.9, 210.9 ± 20.9, 39.6 ± 11.9 and 4.0 ± 0.9, respectively. A blocking study was also performed by co-injection of excess amount of non-radioactive Ga-coupled of CCZ01048, which confirmed that the tumor uptake was MC1R mediated. In conclusion, the introduction of a cationic Pip linker to Nle-CycMSHhex, CCZ01048, not only improved tumor uptake, but also generated high tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model. Therefore, CCZ01048 is a promising candidate for PET imaging of melanoma, and potentially as a theranostic agent for radionuclide therapy of melanoma when labeled with α or β emitters.
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Zhengxing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada; Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Jinhe
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Iulia
authors.initials: I
authors.lastname: Dude
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Navjit
authors.initials: N
authors.lastname: Hundal-Jabal
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Colpo
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada; Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Bénard
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005710:Gallium Radioisotopes / Q000008:administration & dosage*; D008545:Melanoma / Q000000981:diagnostic imaging*; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography / Q000379:methods*; D013194:Staining and Labeling; D000521:alpha-MSH / Q000008:administration & dosage* / Q000031:analogs & derivatives*
chemical_list: D005710:Gallium Radioisotopes; D000521:alpha-MSH
keywords: Ga-68.; Melanocortin 1 receptor; Melanoma; PET imaging; α-melanocyte-stimulating hormone