{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:38:04Z","timestamp":1787164684738,"version":"build-2736575974"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004012","name":"Jane ja Aatos Erkon S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004012","id-type":"DOI","asserted-by":"publisher"}]},{"name":"State Research Funding ERVA","award":["11009"],"award-info":[{"award-number":["11009"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Imaging Biol"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      The glutamine analogue (2\n                      <jats:italic>S<\/jats:italic>\n                      , 4\n                      <jats:italic>R<\/jats:italic>\n                      )-4-[\n                      <jats:sup>18<\/jats:sup>\n                      F]fluoroglutamine ([\n                      <jats:sup>18<\/jats:sup>\n                      F]FGln) was investigated to further characterize its pharmacokinetics and acquire\n                      <jats:italic>in vivo<\/jats:italic>\n                      positron emission tomography (PET) images of separate orthotopic and subcutaneous glioma xenografts in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Procedures<\/jats:title>\n                    <jats:p>\n                      [\n                      <jats:sup>18<\/jats:sup>\n                      F]FGln was synthesized at a high radiochemical purity as analyzed by high-performance liquid chromatography. An orthotopic model was created by injecting luciferase-expressing patient-derived BT3 glioma cells into the right hemisphere of BALB\/cOlaHsd-Foxn1\n                      <jats:sup>nu<\/jats:sup>\n                      mouse brains (tumor growth monitored\n                      <jats:italic>via in vivo<\/jats:italic>\n                      bioluminescence), the subcutaneous model by injecting rat BT4C glioma cells into the flank and neck regions of Foxn1\n                      <jats:sup>nu\/nu<\/jats:sup>\n                      mice. Dynamic PET images were acquired after injecting 10\u201312\u00a0MBq of the tracer into mouse tail veins. Animals were sacrificed 63\u00a0min after tracer injection, and\n                      <jats:italic>ex vivo<\/jats:italic>\n                      biodistributions were measured. Tumors and whole brains (with tumors) were cryosectioned, autoradiographed, and stained with hematoxylin-eosin. All images were analyzed with CARIMAS software. Blood sampling of 6 Foxn1\n                      <jats:sup>nu\/nu<\/jats:sup>\n                      and 6 C57BL\/6J mice was performed after 9\u201314\u00a0MBq of tracer was injected at time points between 5 and 60\u00a0min then assayed for erythrocyte uptake, plasma protein binding, and plasma parent-fraction of radioactivity to correct PET image-derived whole-blood radioactivity and apply the data to multiple pharmacokinetic models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Orthotopic human glioma xenografts displayed PET image tumor-to-healthy brain region ratio of 3.6 and 4.8 while subcutaneously xenografted BT4C gliomas displayed (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200912) a tumor-to-muscle (flank) ratio of 1.9\u2009\u00b1\u20090.7 (range 1.3\u20133.4). Using PET image-derived blood radioactivity corrected by population-based stability analyses, tumor uptake pharmacokinetics fit Logan and Yokoi modeling for reversible uptake.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The results reinforce that [\n                      <jats:sup>18<\/jats:sup>\n                      F]FGln has preferential uptake in glioma tissue\n                      <jats:italic>versus<\/jats:italic>\n                      that of corresponding healthy tissue and fits well with reversible uptake models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11307-020-01472-1","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T17:10:32Z","timestamp":1580231432000},"page":"969-978","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["(2S, 4R)-4-[18F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models"],"prefix":"10.1007","volume":"22","author":[{"given":"Maxwell WG","family":"Miner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Liljenb\u00e4ck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenni","family":"Virta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joni","family":"Merisaari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesa","family":"Oikonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka","family":"Westermarck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Guo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-7977","authenticated-orcid":false,"given":"Anne","family":"Roivainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,28]]},"reference":[{"key":"1472_CR1","doi-asserted-by":"publisher","first-page":"94871","DOI":"10.1371\/journal.pone.0094871","volume":"9","author":"N Lin","year":"2014","unstructured":"Lin N, Yan W, Gao K et al (2014) Prevalence and clinicopathologic characteristics of the molecular subtypes in malignant glioma: a multi-institutional analysis of 941 cases. PLoS One 9:94871","journal-title":"PLoS One"},{"key":"1472_CR2","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1002\/ana.10679","volume":"54","author":"M Platten","year":"2003","unstructured":"Platten M, Kretz A, Naumann U et al (2003) Monocyte chemoattractant protein\u20131 increases microglial infiltration and aggressiveness of gliomas. Ann Neurol 54:388\u2013392","journal-title":"Ann Neurol"},{"key":"1472_CR3","doi-asserted-by":"publisher","first-page":"2051","DOI":"10.1200\/JCO.2009.26.5520","volume":"28","author":"JR Perry","year":"2010","unstructured":"Perry JR, B\u00e9langer K, Mason WP et al (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 28:2051\u20132057","journal-title":"J Clin Oncol"},{"key":"1472_CR4","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1126\/scitranslmed.aaa1009","volume":"7","author":"S Venneti","year":"2015","unstructured":"Venneti S, Dunphy MP, Zhang H et al (2015) Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci Trans Med 7:274","journal-title":"Sci Trans Med"},{"key":"1472_CR5","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1148\/radiol.2017162610","volume":"287","author":"MP Dunphy","year":"2018","unstructured":"Dunphy MP, Harding JJ, Venneti S et al (2018) In vivo PET assay of tumor glutamine flux and metabolism: in-human trial of [18F]-(2S, 4R)-4-fluoroglutamine. Radiology 287:667\u2013675","journal-title":"Radiology"},{"key":"1472_CR6","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.tibs.2010.05.003","volume":"35","author":"DR Wise","year":"2010","unstructured":"Wise DR, Thompson CB (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35:427\u2013433","journal-title":"Trends Biochem Sci"},{"key":"1472_CR7","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/nrc.2016.71","volume":"16","author":"BJ Altman","year":"2016","unstructured":"Altman BJ, Stine ZE, Dang CV (2016) From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16:619","journal-title":"Nat Rev Cancer"},{"key":"1472_CR8","doi-asserted-by":"publisher","first-page":"18782","DOI":"10.1073\/pnas.0810199105","volume":"105","author":"DR Wise","year":"2008","unstructured":"Wise DR, DeBerardinis RJ, Mancuso A et al (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A 105:18782\u201318787","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1472_CR9","doi-asserted-by":"publisher","first-page":"2475","DOI":"10.1093\/jn\/131.9.2475S","volume":"131","author":"BP Bode","year":"2001","unstructured":"Bode BP (2001) Recent molecular advances in mammalian glutamine transport. J Nutr 131:2475\u20132485","journal-title":"J Nutr"},{"key":"1472_CR10","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S0968-0004(01)02054-0","volume":"27","author":"D Wipf","year":"2002","unstructured":"Wipf D, Ludewig U, Tegeder M et al (2002) Conservation of amino acid transporters in fungi, plants and animals. Trends Biochem Sci 27:139\u2013147","journal-title":"Trends Biochem Sci"},{"key":"1472_CR11","doi-asserted-by":"publisher","first-page":"98","DOI":"10.2967\/jnumed.111.093831","volume":"53","author":"W Qu","year":"2012","unstructured":"Qu W, Oya S, Lieberman BP et al (2012) Preparation and characterization of l-[5-11C]-glutamine for metabolic imaging of tumors. J Nucl Med 53:98\u2013105","journal-title":"J Nucl Med"},{"key":"1472_CR12","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1097\/RLU.0000000000000487","volume":"39","author":"S Hess","year":"2014","unstructured":"Hess S, H\u00f8ilund-Carlsen PF, Alavi A (2014) Historic images in nuclear medicine: 1976: the first issue of clinical nuclear medicine and the first human FDG study. Clin Nucl Med 39:701\u2013703","journal-title":"Clin Nucl Med"},{"key":"1472_CR13","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.tins.2013.07.001","volume":"36","author":"P Mergenthaler","year":"2013","unstructured":"Mergenthaler P, Lindauer U, Dienel GA, Meisel A (2013) Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 36:587\u2013597","journal-title":"Trends Neurosci"},{"key":"1472_CR14","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1002\/ana.410340113","volume":"34","author":"J Pujol","year":"1993","unstructured":"Pujol J, Vendrell P, Junqu\u00e9 C, Mart\u00ed-Vilalta JL, Capdevila A (1993) When does human brain development end? Evidence of corpus callosum growth up to adulthood. Ann Neurol 34:71\u201375","journal-title":"Ann Neurol"},{"key":"1472_CR15","first-page":"411","volume":"46","author":"D Pauleit","year":"2005","unstructured":"Pauleit D, Stoffels G, Schaden W et al (2005) PET with o-(2-18F-fluoroethyl)-l-tyrosine in peripheral tumors: first clinical results. J Nucl Med 46:411\u2013416","journal-title":"J Nucl Med"},{"key":"1472_CR16","doi-asserted-by":"publisher","first-page":"573","DOI":"10.2967\/jnumed.107.045708","volume":"49","author":"PL Jager","year":"2008","unstructured":"Jager PL, Chirakal R, Marriott CJ et al (2008) 6-L-18F-fluorodihydroxyphenylalanine PET in neuroendocrine tumors: basic aspects and emerging clinical applications. J Nucl Med 49:573\u2013586","journal-title":"J Nucl Med"},{"key":"1472_CR17","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/s11060-010-0117-9","volume":"99","author":"S Okubo","year":"2010","unstructured":"Okubo S, Zhen HN, Kawai N et al (2010) Correlation of L-methyl-11C-methionine (Met) uptake with l-type amino acid transporter 1 in human gliomas. J Neur Onc 99:217\u2013225","journal-title":"J Neur Onc"},{"key":"1472_CR18","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1212\/WNL.50.5.1316","volume":"50","author":"K Herholz","year":"1998","unstructured":"Herholz K, H\u00f6lzer T, Bauer B et al (1998) 11C-methionine PET for differential diagnosis of low-grade gliomas. Neurology 50:1316\u20131322","journal-title":"Neurology"},{"key":"1472_CR19","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1097\/RLU.0000000000002638","volume":"44","author":"C Lapa","year":"2019","unstructured":"Lapa C, Kircher M, Da Via M et al (2019) Comparison of 11C-choline and 11C-methionine PET\/CT in multiple myeloma. Clin Nucl Med 44:620\u2013624","journal-title":"Clin Nucl Med"},{"key":"1472_CR20","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s12079-015-0315-5","volume":"10","author":"SD Yelamanchi","year":"2016","unstructured":"Yelamanchi SD, Jayaram S, Thomas JK et al (2016) A pathway map of glutamate metabolism. J Cell Commun Signal 10:69\u201375","journal-title":"J Cell Commun Signal"},{"key":"1472_CR21","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/0026-0495(92)90186-E","volume":"41","author":"V Grill","year":"1992","unstructured":"Grill V, Bj\u00f6rkman O, Gutniak M, Lindqvist M (1992) Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: important role of glutamine release for nitrogen balance. Metabolism 41:28\u201332","journal-title":"Metabolism"},{"key":"1472_CR22","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.2967\/jnumed.111.093815","volume":"52","author":"BP Lieberman","year":"2011","unstructured":"Lieberman BP, Ploessl K, Wang L et al (2011) PET imaging of glutaminolysis in tumors by 18F-(2S, 4R) 4-fluoroglutamine. J Nucl Med 52:1947\u20131955","journal-title":"J Nucl Med"},{"key":"1472_CR23","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1007\/s11307-015-0862-4","volume":"18","author":"M Hassanein","year":"2016","unstructured":"Hassanein M, Hight MR, Buck JR et al (2016) Preclinical evaluation of 4-[18F]fluoroglutamine PET to assess ASCT2 expression in lung cancer. Mol Imaging Biol 18:18\u201323","journal-title":"Mol Imaging Biol"},{"key":"1472_CR24","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1158\/0008-5472.CAN-16-1945","volume":"77","author":"R Zhou","year":"2017","unstructured":"Zhou R, Pantel AR, Li S et al (2017) [18F](2S, 4R)4-fluoroglutamine PET detects glutamine pool size changes in triple-negative breast cancer in response to glutaminase inhibition. Cancer Res 77:1476\u20131484","journal-title":"Cancer Res"},{"key":"1472_CR25","doi-asserted-by":"publisher","first-page":"3852","DOI":"10.1021\/mp500236y","volume":"11","author":"Z Wu","year":"2014","unstructured":"Wu Z, Zha Z, Li G et al (2014) [18F](2S,4R)-4-(3-fluoropropyl)glutamine as a tumor imaging agent. Mol Pharm 11:3852\u20133866","journal-title":"Mol Pharm"},{"key":"1472_CR26","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.nucmedbio.2018.02.001","volume":"60","author":"Z Zha","year":"2018","unstructured":"Zha Z, Ploessl K, Lieberman BP et al (2018) Alanine and glycine conjugates of (2S,4R)-4-[18F]fluoroglutamine for tumor imaging. Nucl Med Biol 60:19\u201328","journal-title":"Nucl Med Biol"},{"key":"1472_CR27","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.nucmedbio.2018.06.007","volume":"64","author":"C Li","year":"2018","unstructured":"Li C, Liu H, Duan D et al (2018) Preclinical study of an 18F-labeled glutamine derivative for cancer imaging. Nucl Med Biol 64:34\u201340","journal-title":"Nucl Med Biol"},{"key":"1472_CR28","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1038\/nprot.2013.170","volume":"9","author":"XG Li","year":"2014","unstructured":"Li XG, Helariutta K, Roivainen A et al (2014) Using 5-deoxy-5-[18F] fluororibose to glycosylate peptides for positron emission tomography. Nat Protoc 9:138\u2013145","journal-title":"Nat Protoc"},{"key":"1472_CR29","doi-asserted-by":"crossref","unstructured":"Le Joncour V, Filppu P, Hyv\u00f6nen M, et al. (2019) Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization. EMBO Mol Med 11:pii:e9034","DOI":"10.15252\/emmm.201809034"},{"key":"1472_CR30","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1007\/s00259-018-4207-9","volume":"46","author":"I Law","year":"2019","unstructured":"Law I, Albert NL, Arbizu J et al (2019) Joint EANM\/EANO\/RANO practice guidelines\/SNMMI procedure standards for imaging of gliomas using pet with radiolabelled amino acids and [18F]FDG: v 1.0. Eur J Nucl Med Mol Imaging 46:540\u2013557","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"1472_CR31","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1093\/bja\/54.8.871","volume":"54","author":"S Bower","year":"1982","unstructured":"Bower S, Hull CJ (1982) Comparative pharmacokinetics of fentanyl and alfentanil. Br J Anaesth 54:871\u2013877","journal-title":"Br J Anaesth"},{"key":"1472_CR32","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.cbpb.2012.05.010","volume":"163","author":"AJ Cooper","year":"2012","unstructured":"Cooper AJ, Krasnikov BF, Pinto JT et al (2012) Comparative enzymology of (2S, 4R) 4-fluoroglutamine and (2S, 4R)4-fluoroglutamate. Comp Biochem Physiol, Part B: Biochem Mol Biol 163:108\u2013120","journal-title":"Comp Biochem Physiol, Part B: Biochem Mol Biol"},{"key":"1472_CR33","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.cmet.2018.05.021","volume":"28","author":"S Della Torre","year":"2018","unstructured":"Della Torre S, Mitro N, Meda C et al (2018) Short-term fasting reveals amino acid metabolism as a major sex-discriminating factor in the liver. Cell Metab 28:256\u2013267","journal-title":"Cell Metab"},{"key":"1472_CR34","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1126\/science.1140485","volume":"317","author":"WE Naugler","year":"2007","unstructured":"Naugler WE, Sakurai T, Kim S et al (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121\u2013124","journal-title":"Science"}],"container-title":["Molecular Imaging and Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11307-020-01472-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s11307-020-01472-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11307-020-01472-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T19:15:58Z","timestamp":1611688558000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s11307-020-01472-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,28]]},"references-count":34,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["1472"],"URL":"https:\/\/doi.org\/10.1007\/s11307-020-01472-1","relation":{},"ISSN":["1536-1632","1860-2002"],"issn-type":[{"value":"1536-1632","type":"print"},{"value":"1860-2002","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,28]]},"assertion":[{"value":"28 January 2020","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}