{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T04:53:55Z","timestamp":1780721635950,"version":"3.54.1"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100015539","name":"Australian Government","doi-asserted-by":"publisher","award":["Collaborative Research Consortium Grant 2005-2012"],"award-info":[{"award-number":["Collaborative Research Consortium Grant 2005-2012"]}],"id":[{"id":"10.13039\/100015539","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001782","name":"University of Melbourne","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001782","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Imaging Biol"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Malignant melanoma is a highly lethal malignancy typically characterized by the expression of melanin, which is an attractive diagnostic and therapeutic target in these cancers because it is expressed in few other tissues. Following preclinical evaluation of the melanin-targeting PET tracer, [18F]-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide ([18F]MEL050), we sought to evaluate this agent in patients with melanoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>A phase I clinical trial was performed in ten patients with metastatic melanoma. Safety, dosimetry and diagnostic performance of intravenously administered][18F]MEL050 were evaluated. Based on results from this trial, we further assessed the prevalence and prognostic significance of loss of melanin expression in two historical patient cohorts for which there were matching histological and clinical outcome data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Across the trial cohort, no adverse safety signals resulted from [18F]MEL050 administration. The whole-body effective dose was 0.0163 mSV\/MBq for an adult male and 0.0206 mSV\/MBq for an adult female. The human biodistribution was favorable with low uptake in organs at high risk of metastatic spread, including the brain. Of metastatic sites identified as melanoma on [18F]FDG PET\/CT, only 31\/65 (48%) were positive on [18F]MEL050 PET. Four [18F]FDG+[18F]MEL050+ metastases were resected from three patients and found to be melanotic by histological examination, whereas five [18F]FDG+[18F]MEL050- metastases from two patients were amelanotic. In our historical cohorts, amelanosis was more common in metastatic than primary disease (45% versus 20%) and the presence of melanin within sentinel lymph node metastases was associated with worse disease-free (HR 2.3 95% CI 1.3 - 4.3,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.002) and disease-specific survivals (HR 3.6, 95% CI 1.4 - 9.7,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.009) in stage III disease, compared with amelanotic sentinel lymph node metastases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We propose caution in the use of melanin-targeted agents for melanoma diagnosis and therapy until their utility as prognostic or predictive imaging biomarkers, and the biological implications of loss of melanin deposition during melanoma progression, are better understood.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11307-025-02025-0","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T13:38:14Z","timestamp":1750340294000},"page":"649-657","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Poor Diagnostic Performance of the Melanin-Binding Tracer [18 F]MEL050 in Human Melanoma Indicates Biological Heterogeneity"],"prefix":"10.1007","volume":"27","author":[{"given":"Robert E.","family":"Ware","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Kee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Roselt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Greguric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Katsifis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bourdier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne","family":"Noonan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marnie","family":"Downes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Shackleton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant A.","family":"McArthur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0758-0824","authenticated-orcid":false,"given":"Rodney J.","family":"Hicks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"issue":"10304","key":"2025_CR1","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/S0140-6736(21)01206-X","volume":"398","author":"MS Carlino","year":"2021","unstructured":"Carlino MS, Larkin J, Long GV (2021) Immune checkpoint inhibitors in melanoma. Lancet 398(10304):1002\u20131014","journal-title":"Lancet"},{"issue":"8","key":"2025_CR2","doi-asserted-by":"publisher","first-page":"e2327145","DOI":"10.1001\/jamanetworkopen.2023.27145","volume":"6","author":"RS Goodman","year":"2023","unstructured":"Goodman RS et al (2023) Extended follow-up of chronic immune-related adverse events following adjuvant anti-PD-1 therapy for high-risk resected melanoma. JAMA Netw Open 6(8):e2327145","journal-title":"JAMA Netw Open"},{"key":"2025_CR3","doi-asserted-by":"publisher","first-page":"103044","DOI":"10.1016\/j.critrevonc.2020.103044","volume":"153","author":"C Bisschop","year":"2020","unstructured":"Bisschop C et al (2020) Rational use of 18F-FDG PET\/CT in patients with advanced cutaneous melanoma: A systematic review. Crit Rev Oncol Hematol 153:103044","journal-title":"Crit Rev Oncol Hematol"},{"issue":"7","key":"2025_CR4","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1093\/annonc\/mdy124","volume":"29","author":"J Lewin","year":"2018","unstructured":"Lewin J et al (2018) Surveillance imaging with FDG-PET\/CT in the post-operative follow-up of stage 3 melanoma. Ann Oncol 29(7):1569\u20131574","journal-title":"Ann Oncol"},{"issue":"9","key":"2025_CR5","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1007\/s002590050302","volume":"25","author":"EM Link","year":"1998","unstructured":"Link EM et al (1998) Early detection of melanoma metastases with radioiodinated methylene blue. Eur J Nucl Med 25(9):1322\u20131329","journal-title":"Eur J Nucl Med"},{"issue":"3","key":"2025_CR6","first-page":"299","volume":"9","author":"S Beatovi\u0107","year":"2004","unstructured":"Beatovi\u0107 S et al (2004) Diagnosis and follow up of primary ocular melanoma by radioimmunoscintigraphy. J BUON 9(3):299\u2013302","journal-title":"J BUON"},{"issue":"3","key":"2025_CR7","first-page":"404","volume":"47","author":"K Kato","year":"2006","unstructured":"Kato K et al (2006) Low efficacy of 18F-FDG PET for detection of uveal malignant melanoma compared with 123I-IMP SPECT. J Nucl Med 47(3):404\u2013409","journal-title":"J Nucl Med"},{"issue":"3","key":"2025_CR8","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.nucmedbio.2009.01.003","volume":"36","author":"H Guo","year":"2009","unstructured":"Guo H et al (2009) Metastatic melanoma imaging with an 111In-labeled lactam bridge-cyclized alpha-melanocyte-stimulating hormone peptide. Nucl Med Biol 36(3):267\u2013276","journal-title":"Nucl Med Biol"},{"issue":"5","key":"2025_CR9","doi-asserted-by":"publisher","first-page":"823","DOI":"10.2967\/jnumed.107.048553","volume":"49","author":"Y Miao","year":"2008","unstructured":"Miao Y et al (2008) 203Pb-labeled alpha-melanocyte-stimulating hormone peptide as an imaging probe for melanoma detection. J Nucl Med 49(5):823\u2013829","journal-title":"J Nucl Med"},{"issue":"1","key":"2025_CR10","doi-asserted-by":"publisher","first-page":"15","DOI":"10.2967\/jnumed.113.123554","volume":"55","author":"F Cachin","year":"2014","unstructured":"Cachin F et al (2014) 123I-BZA2 as a melanin-targeted radiotracer for the identification of melanoma metastases: results and perspectives of a multicenter phase III clinical trial. J Nucl Med 55(1):15\u201322","journal-title":"J Nucl Med"},{"issue":"5","key":"2025_CR11","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1002\/ijc.28103","volume":"133","author":"F Degoul","year":"2013","unstructured":"Degoul F et al (2013) In vivo efficacy of melanoma internal radionuclide therapy with a 131I-labelled melanin-targeting heteroarylcarboxamide molecule. Int J Cancer 133(5):1042\u20131053","journal-title":"Int J Cancer"},{"issue":"11","key":"2025_CR12","doi-asserted-by":"publisher","first-page":"3133","DOI":"10.1021\/jm701424g","volume":"51","author":"JM Chezal","year":"2008","unstructured":"Chezal JM et al (2008) Evaluation of radiolabeled (hetero)aromatic analogues of N-(2-diethylaminoethyl)-4-iodobenzamide for imaging and targeted radionuclide therapy of melanoma. J Med Chem 51(11):3133\u20133144","journal-title":"J Med Chem"},{"issue":"8","key":"2025_CR13","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.2967\/jnumed.107.041673","volume":"48","author":"TQ Pham","year":"2007","unstructured":"Pham TQ et al (2007) Preparation and biologic evaluation of a novel radioiodinated benzylpiperazine, 123I-MEL037, for malignant melanoma. J Nucl Med 48(8):1348\u20131356","journal-title":"J Nucl Med"},{"issue":"11","key":"2025_CR14","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1007\/s00259-002-0971-6","volume":"29","author":"N Moins","year":"2002","unstructured":"Moins N et al (2002) 123I-N-(2-diethylaminoethyl)-2-iodobenzamide: a potential imaging agent for cutaneous melanoma staging. Eur J Nucl Med Mol Imaging 29(11):1478\u20131484","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"1","key":"2025_CR15","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/S0181-5512(04)96089-5","volume":"27","author":"I Sillaire-Houtmann","year":"2004","unstructured":"Sillaire-Houtmann I et al (2004) Phase 2 clinical study of 123I-N-(2-diethylaminoethyl)-2-iodobenzamide in the diagnostic of primary and metastatic ocular melanoma. J Fr Ophtalmol 27(1):34\u201339","journal-title":"J Fr Ophtalmol"},{"issue":"3","key":"2025_CR16","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1021\/bc8005094","volume":"20","author":"S Garg","year":"2009","unstructured":"Garg S et al (2009) Design, synthesis, and preliminary in vitro and in vivo evaluation of N-(2-diethylaminoethyl)-4-[18F]fluorobenzamide ([18F]-DAFBA): a novel potential PET probe to image melanoma tumors. Bioconjug Chem 20(3):583\u2013590","journal-title":"Bioconjug Chem"},{"issue":"17","key":"2025_CR17","doi-asserted-by":"publisher","first-page":"5299","DOI":"10.1021\/jm9008423","volume":"52","author":"I Greguric","year":"2009","unstructured":"Greguric I et al (2009) Discovery of [18F]N-(2-(diethylamino)ethyl)-6-fluoronicotinamide: a melanoma positron emission tomography imaging radiotracer with high tumor to body contrast ratio and rapid renal clearance. J Med Chem 52(17):5299\u20135302","journal-title":"J Med Chem"},{"issue":"3","key":"2025_CR18","doi-asserted-by":"publisher","first-page":"441","DOI":"10.2967\/jnumed.109.070060","volume":"51","author":"D Denoyer","year":"2010","unstructured":"Denoyer D et al (2010) High-contrast PET of melanoma using 18F-MEL050, a selective probe for melanin with predominantly renal clearance. J Nucl Med 51(3):441\u2013447","journal-title":"J Nucl Med"},{"issue":"1","key":"2025_CR19","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s00259-015-3134-2","volume":"43","author":"H Feng","year":"2016","unstructured":"Feng H et al (2016) Imaging malignant melanoma with 18F-5-FPN. Eur J Nucl Med Mol Imaging 43(1):113\u2013122","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"1","key":"2025_CR20","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1007\/s00259-023-06439-2","volume":"51","author":"X Zhang","year":"2023","unstructured":"Zhang X et al (2023) Melanin-targeted [18F]-PFPN PET imaging for prognosticating patients with melanoma. Eur J Nucl Med Mol Imaging 51(1):196\u2013201","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"11","key":"2025_CR21","doi-asserted-by":"publisher","first-page":"3896","DOI":"10.1021\/acs.molpharmaceut.7b00607","volume":"14","author":"X Xu","year":"2017","unstructured":"Xu X et al (2017) Synthesis and preclinical evaluation of 18F-PEG3-FPN for the detection of metastatic pigmented melanoma. Mol Pharm 14(11):3896\u20133905","journal-title":"Mol Pharm"},{"issue":"1","key":"2025_CR22","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1148\/radiol.2511081300","volume":"251","author":"B Huang","year":"2009","unstructured":"Huang B, Law MW, Khong PL (2009) Whole-body PET\/CT scanning: estimation of radiation dose and cancer risk. Radiology 251(1):166\u2013174","journal-title":"Radiology"},{"issue":"Suppl 1","key":"2025_CR23","first-page":"S51","volume":"44","author":"G Brix","year":"2005","unstructured":"Brix G, Beyer T (2005) PET\/CT: dose-escalated image fusion? Nuklearmedizin 44(Suppl 1):S51\u2013S57","journal-title":"Nuklearmedizin"},{"issue":"10","key":"2025_CR24","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.2967\/jnumed.121.263179","volume":"63","author":"X Zhang","year":"2022","unstructured":"Zhang X et al (2022) F-PFPN PET: a new and attractive imaging modality for patients with malignant melanoma. J Nucl Med 63(10):1537\u20131543","journal-title":"J Nucl Med"},{"issue":"2","key":"2025_CR25","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/S0733-8635(18)30901-X","volume":"3","author":"RJ Friedman","year":"1985","unstructured":"Friedman RJ, Rigel DS (1985) The clinical features of malignant melanoma. Dermatol Clin 3(2):271\u2013283","journal-title":"Dermatol Clin"},{"issue":"15","key":"2025_CR26","doi-asserted-by":"publisher","first-page":"6214","DOI":"10.1021\/acs.jmedchem.5b00777","volume":"58","author":"MP Roberts","year":"2015","unstructured":"Roberts MP et al (2015) Synthesis and in vivo evaluation of [123i]melanin-targeted agents. J Med Chem 58(15):6214\u20136224","journal-title":"J Med Chem"},{"issue":"7","key":"2025_CR27","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/s41568-019-0154-4","volume":"19","author":"I Arozarena","year":"2019","unstructured":"Arozarena I, Wellbrock C (2019) Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat Rev Cancer 19(7):377\u2013391","journal-title":"Nat Rev Cancer"}],"container-title":["Molecular Imaging and Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11307-025-02025-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11307-025-02025-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11307-025-02025-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T20:29:52Z","timestamp":1757190592000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11307-025-02025-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":27,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["2025"],"URL":"https:\/\/doi.org\/10.1007\/s11307-025-02025-0","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-4844701\/v1","asserted-by":"object"}]},"ISSN":["1536-1632","1860-2002"],"issn-type":[{"value":"1536-1632","type":"print"},{"value":"1860-2002","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]},"assertion":[{"value":"1 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 May 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"No authors declare conflicts of interest relevant to this manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"PMCC HREC # 10\/11PMCC HREC #12\/74","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approvals"}}]}}