Al18F-labeled alpha-melanocyte-stimulating hormone (α-MSH) peptide derivative for the early detection of melanoma

  • Citra R. A. P. Palangka
  • Hirofumi HanaokaEmail author
  • Aiko Yamaguchi
  • Takashi Murakami
  • Yoshito Tsushima
Original Article



Early detection plays a role in the prognosis of melanoma, the most aggressive skin cancer. 64Cu- and 68Ga-labeled alpha-melanocyte-stimulating hormone (α-MSH) analogs targeting the melanocortin-1 receptor are promising positron emission tomography (PET) tracers for detecting melanoma, and the use of 18F-labeling will further contribute to the detectability and availability. However, the high radiochemistry demand related to the conventional 18F-labeling methods has restricted the development of 18F-labeled α-MSH analogs. A recently developed radiofluorination method using aluminum-fluoride (Al18F) offers a simple, efficient, and time-saving labeling procedure compared to the conventional 18F-labeling methods. Herein, we sought to establish a simple preparation method for an 18F-labeled α-MSH analog using Al18F, and we examined its potential for the early detection of melanoma.


A 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA)-conjugated α-MSH analog (NOTA-GGNle-CycMSHhex) was prepared by the Fmoc solid-phase strategy. NOTA-GGNle-CycMSHhex was labeled with Al18F by heating at 105 °C using a microwave synthesizer for 15 min. Biodistribution study was conducted on B16/F10-luc melanoma-bearing mice at 30 min, 1 h and 3 h after injection of Al18F-NOTA-GGNle-CycMSHhex. PET imaging was conducted on melanoma-bearing mice at 1 h post-injection. One day prior to the PET imaging, bioluminescence imaging was also performed.


Al18F-NOTA-GGNle-CycMSHhex was readily prepared with a high radiochemical yield (94.0 ± 2.8%). The biodistribution study showed a high accumulation of Al18F-NOTA-GGNle-CycMSHhex in the tumor at 30 min and 1 h post-injection (6.69 ± 1.49 and 7.70 ± 1.71%ID/g, respectively). The tumor-to-blood ratio increased with time: 3.46 ± 0.89, 12.67 ± 1.29, and 35.27 ± 9.12 at 30 min, 1 h, and 3 h post-injection, respectively. In the PET imaging, Al18F-NOTA-GGNle-CycMSHhex clearly visualized the tumors and depicted very small tumors (< 3 mm).


We successfully prepared Al18F-NOTA-GGNle-CycMSHhex in a simple and efficient manner. Al18F-NOTA-GGNle-CycMSHhex showed high tumor accumulation and clearly visualized very small tumors in melanoma-bearing mice. These findings suggest that Al18F-NOTA-GGNle-CycMSHhex will be a promising PET tracer for melanoma imaging at an earlier stage.


Melanoma PET Alpha-melanocyte-stimulating hormone Fluoride–aluminum chelate Peptide 



  1. 1.
    Apalla Z, Lallas A, Sotiriou E, Lazaridou E, Ioannides D. Epidemiological trends in skin cancer. Dermatol Pract Concept. 2017;7:1–6.CrossRefGoogle Scholar
  2. 2.
    Huff LS, Chang CA, Thomas JF, Cook-Shimanek MK, Blomquist P, Konnikov N, et al. Defining an acceptable period of time from melanoma biopsy to excision. Dermatol Rep. 2012;4:e2.CrossRefGoogle Scholar
  3. 3.
    Danielsen M, Højgaard L, Kjær A, Fischer BM. Positron emission tomography in the follow-up of cutaneous malignant melanoma patients: a systematic review. Am J Nucl Med Mol Imaging. 2013;4:17–28.Google Scholar
  4. 4.
    Xing Y, Bronstein Y, Ross MI, Askew RL, Lee JE, Gershenwald JE, et al. Contemporary diagnostic imaging modalities for the staging and surveillance of melanoma patients: a meta-analysis. J Natl Cancer Inst. 2011;103:129–42.CrossRefGoogle Scholar
  5. 5.
    Pilat P, Borzecki A, Jazienicki M, Krasowska D. Skin melanoma imaging using ultrasonography: a literature review. Postep Dermatol Alergol. 2018;35:238–42.CrossRefGoogle Scholar
  6. 6.
    Crippa F, Leutner M, Belli F, Gallino F, Greco M, Pilotti S, et al. Which kinds of lymph node metastases can FDG PET detect? A clinical study in melanoma. J Nucl Med. 2000;41:1491–4.Google Scholar
  7. 7.
    Mijnhout GS, Hoekstra OS, van Tulder MW, Teule GJ, Devillé WL. Systematic review of the diagnostic accuracy of 18F-fluorodeoxyglucose positron emission tomography in melanoma patients. Cancer. 2001;91:1530–42.CrossRefGoogle Scholar
  8. 8.
    Tchernev G, Popova LV. PET scan misses cutaneous melanoma metastasis with significant tumour size and tumour thickness. Open Access Maced J Med Sci. 2017;5:963–6.Google Scholar
  9. 9.
    Uğurluer G, Kibar M, Yavuz S, Kuzucu A, Serin M. False positive 18F-FDG uptake in mediastinal lymph nodes detected with positron emission tomography in breast cancer: a case report. Case Rep Med. 2013;2013:459753.Google Scholar
  10. 10.
    Dimitrakopoulou-Strauss A, Strauss LG, Burger C. Quantitative PET studies in pretreated melanoma patients: a comparison of 6-[18F]fluoro-l-dopa with 18F-FDG and 15O-water using compartment and noncompartment analysis. J Nucl Med. 2001;42:248–56.Google Scholar
  11. 11.
    Guo H, Shenoy N, Gershman BM, Yang J, Sklar LA, Miao Y. Metastatic melanoma imaging with an 111In-labeled lactam bridge-cyclized α-melanocyte-stimulating hormone peptide. Nucl Med Biol. 2009;36:267–76.CrossRefGoogle Scholar
  12. 12.
    Quinn T, Zhang X, Miao Y. Targeted melanoma imaging and therapy with radiolabeled alpha-melanocyte stimulating hormone peptide analogues. G Ital Dermatol Venereol. 2011;145:245–58.Google Scholar
  13. 13.
    Miao Y, Benwell K, Quinn TP. 99mTc- and 111In-labeled alpha-melanocyte-stimulating hormone peptides as imaging probes for primary and pulmonary metastatic melanoma detection. J Nucl Med. 2007;48:73–81.Google Scholar
  14. 14.
    Siegrist W, Solca F, Stutz S, Giuffrè L, Carrel S, Girard J, et al. Characterization of receptors for α-melanocyte-stimulating hormone on human melanoma cells. Cancer Res. 1989;49:6352–8.Google Scholar
  15. 15.
    Guo H, Miao Y. Cu-64-labeled lactam bridge-cyclized α-MSH peptides for PET imaging of melanoma. Mol Pharm. 2012;9:2322–30.CrossRefGoogle Scholar
  16. 16.
    Guo H, Gallazzi F, Miao Y. Gallium-67-labeled lactam bridge-cyclized alpha-MSH peptides with enhanced melanoma uptake and reduced renal uptake. Bioconjug Chem. 2012;23:1341–8.CrossRefGoogle Scholar
  17. 17.
    Orbay H, Zhang Y, Valdovinos HF, Song G, Hernandez R, Theuer CP, et al. Positron emission tomography imaging of CD105 expression in a rat myocardial infarction model with 64Cu-NOTA-TRC105. Am J Nucl Med Mol Imaging. 2013;4:1–9.Google Scholar
  18. 18.
    Decristoforo C, Pickett RD, Verbruggen A. Feasibility and availability of 68Ga-labelled peptides. Eur J Nucl Med Mol Imaging. 2012;39:S31–40.CrossRefGoogle Scholar
  19. 19.
    Pfeifer A, Knigge U, Binderup T, Mortensen J, Oturai P, Loft A, et al. 64Cu-DOTATATE PET for neuroendocrine tumors: a prospective head-to-head comparison with 111In-DTPA-Octreotide in 112 patients. J Nucl Med. 2015;56:847–54.CrossRefGoogle Scholar
  20. 20.
    Zhang C, Zhang Z, Lin KS, Lau J, Zeisler J, Colpo N, et al. Melanoma imaging using 18F-Labeled α-melanocyte-stimulating hormone derivatives with positron emission tomography. Mol Pharm. 2018;15:2116–22.CrossRefGoogle Scholar
  21. 21.
    Cai H, Conti PS. RGD-based PET tracers for imaging receptor integrin αvβ3 expression. J Label Compd Radiopharm. 2013;56:264–79.CrossRefGoogle Scholar
  22. 22.
    Preshlock S, Tredwell M, Gouverneur V. 18F-labeling of arenes and heteroarenes for applications in positron emission tomography. Chem Rev. 2016;116:719–66.CrossRefGoogle Scholar
  23. 23.
    Lang L, Li W, Guo N, Ma Y, Zhu L, Kiesewetter DO, et al. Comparison study of [18F]FAl-NOTA-PRGD2, [18F] FPPRGD2, and [68Ga]Ga-NOTA-PRGD2 for PET imaging of U87MG tumors in mice. Bioconjug Chem. 2011;22:2415–22.CrossRefGoogle Scholar
  24. 24.
    McBride WJ, D’Souza CA, Sharkey RM, Karacay H, Rossi EA, Chang CH, et al. Improved 18F labeling of peptides with a fluoride-aluminum-chelate complex. Bioconjug Chem. 2010;21:1331–40.CrossRefGoogle Scholar
  25. 25.
    Wan W, Guo N, Pan D, Yu C, Weng Y, Luo S, et al. First experience of 18F-alfatide in lung cancer patients using a new lyophilized kit for rapid radiofluorination. J Nucl Med. 2013;54:691–8.CrossRefGoogle Scholar
  26. 26.
    Liu T, Liu C, Xu X, Liu F, Guo X, Li N, et al. Preclinical evaluation and pilot clinical study of Al18F-PSMA-BCH for prostate cancer imaging. J Nucl Med. 2019. Scholar
  27. 27.
    Shamshirian D, Erfani M, Beiki D, Fallahi B, Shafiei M. Development of a 99mTc-labeled lactam bridge-cyclized alpha-MSH derivative peptide as a possible single photon imaging agent for melanoma tumors. Ann Nucl Med. 2015;29:709–20.CrossRefGoogle Scholar
  28. 28.
    Richter S, Wuest F. 18F-labeled peptides: the future is bright. Molecules. 2014;19:20536–56.CrossRefGoogle Scholar
  29. 29.
    Bhattacharyya S, Dixit M. Metallic radionuclides in the development of diagnostic and therapeutic radiopharmaceuticals. Dalton Trans. 2011;40:6112–8.CrossRefGoogle Scholar
  30. 30.
    Shively JE. 18F labeling for immuno-PET: where speed and contrast meet. J Nucl Med. 2007;48:170–2.Google Scholar
  31. 31.
    Jacobson O, Kiesewetter DO, Chen X. Fluorine-18 radiochemistry, labeling strategies and synthetic routes. Bioconjug Chem. 2015;26:1–18.CrossRefGoogle Scholar
  32. 32.
    McBride WJ, Sharkey RM, Karacay H, D’Souza CA, Rossi EA, Laverman P, et al. A novel method of 18F radiolabeling for PET. J Nucl Med. 2009;50:991–8.CrossRefGoogle Scholar
  33. 33.
    Farkas E, Fodor T, Kálmán FK, Tircsó G, Tóth I. Equilibrium and dissociation kinetics of the [Al(NOTA)] complex (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetate). React Kinet Mech Catal. 2015;116:19–33.CrossRefGoogle Scholar
  34. 34.
    Tas F. Metastatic behavior in melanoma: timing, pattern, survival, and influencing factors. J Oncol. 2012;2012:647684.CrossRefGoogle Scholar
  35. 35.
    Patel JK, Didolkar MS, Pickren JW, Moore RH. Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. Am J Surg. 1978;135:807–10.CrossRefGoogle Scholar
  36. 36.
    Tejera-Vaquerizo A, Nagore E, Meléndez JJ, López-Navarro N, Martorell-Calatayud A, Herrera-Acosta E, et al. Chronology of metastasis in cutaneous melanoma: growth rate model. J Invest Dermatol. 2012;132:1215–21.CrossRefGoogle Scholar
  37. 37.
    Gershenwald JE, Scolyer RA. Melanoma staging: American Joint Committee on Cancer (AJCC) 8th edition and beyond. Ann Surg Oncol. 2018;25:2105–10.CrossRefGoogle Scholar
  38. 38.
    Lodge MA, Leal JP, Rahmim A, Sunderland JJ, Frey EC. Measuring PET spatial resolution using a cylinder phantom positioned at an oblique sngle. J Nucl Med. 2018;59:1768–75.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Nuclear Medicine 2019

Authors and Affiliations

  1. 1.Department of Diagnostic Radiology and Nuclear MedicineGunma University Graduate School of MedicineMaebashiJapan
  2. 2.Department of Bioimaging Information AnalysisGunma University Graduate School of MedicineMaebashiJapan
  3. 3.Texas Therapeutics Institute, The Brown Foundation Institute of Molecular MedicineThe University of Texas Health Science Center at HoustonHoustonUSA
  4. 4.Faculty of MedicineSaitama Medical UniversityMoroyamaJapan
  5. 5.Research Program for Diagnostic and Molecular Imaging, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR)Gunma University Graduate School of MedicineMaebashiJapan

Personalised recommendations