title: [(18)F](2S,4S)-4-(3-Fluoropropyl)glutamine as a tumor imaging agent.
abstract: Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [(18)F](2S,4R)- and [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with (18)F and (19)F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[(3)H]glutamine ([(3)H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [(18)F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[(3)H]glutamine and the new probe showed that the uptake of [(3)H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.
authors.affiliation: Departments of Radiology and ‡Pharmacology, University of Pennsylvania , 3700 Market Street, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Zehui
authors.initials: Z
authors.lastname: Wu
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Zha
authors.forename: Genxun
authors.initials: G
authors.lastname: Li
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lieberman
authors.forename: Seok Rye
authors.initials: SR
authors.lastname: Choi
authors.forename: Karl
authors.initials: K
authors.lastname: Ploessl
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D005973:Glutamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D006019:Glycolysis; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013696:Temperature
chemical_list: C000599879:4-(3-fluoropropyl)glutamine; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine
keywords: PET imaging; cancer; glutamine and radiolabeling; metabolism
references.citation: Med Res Rev. 2012 Jul;32(4):868-905
references.pmid: 21793016
references.citation: J Nucl Med. 2011 May;52(5):822-9
references.pmid: 21536930
references.citation: J Nucl Med. 2013 Jul;54(7):1007-10
references.pmid: 23708197
references.citation: Mol Imaging Biol. 2014 Jun;16(3):322-9
references.pmid: 24136390
references.citation: Biochem J. 2004 Aug 15;382(Pt 1):27-32
references.pmid: 15175006
references.citation: Nucl Med Biol. 2006 Apr;33(3):287-94
references.pmid: 16631076
references.citation: J Nucl Med. 2011 Dec;52(12):1947-55
references.pmid: 22095958
references.citation: Cell Metab. 2012 Jan 4;15(1):110-21
references.pmid: 22225880
references.citation: Clin Cancer Res. 2011 Sep 15;17(18):6000-11
references.pmid: 21750203
references.citation: Trends Biochem Sci. 2010 Aug;35(8):427-33
references.pmid: 20570523
references.citation: Nucl Med Biol. 2011 Jan;38(1):53-62
references.pmid: 21220129
references.citation: Radiology. 2014 Mar;270(3):849-56
references.pmid: 24475804
references.citation: J Mol Med (Berl). 2011 Mar;89(3):205-12
references.pmid: 21301795
references.citation: Nucl Med Biol. 2012 Jan;39(1):109-19
references.pmid: 21958853
references.citation: Neuropharmacology. 2005 Nov;49(6):850-61
references.pmid: 16183084
references.citation: Brain Res. 2013 Oct 16;1535:24-37
references.pmid: 23994214
references.citation: Eur J Nucl Med Mol Imaging. 2013 Feb;40(3):394-402
references.pmid: 23208700
references.citation: Semin Cell Dev Biol. 2012 Jun;23(4):362-9
references.pmid: 22349059
references.citation: Arch Biochem Biophys. 2005 Nov 15;443(1-2):53-9
references.pmid: 16197915
references.citation: Nucl Med Biol. 2013 Jul;40(5):670-5
references.pmid: 23647854
references.citation: J Med Chem. 2011 Jan 13;54(1):406-10
references.pmid: 21128591
references.citation: J Am Chem Soc. 2011 Feb 2;133(4):1122-33
references.pmid: 21190335
references.citation: Front Biosci. 2007 Jan 01;12:874-82
references.pmid: 17127344
references.citation: J Nucl Med. 2012 Jan;53(1):98-105
references.pmid: 22173839
references.citation: Nucl Med Biol. 2009 Aug;36(6):681-6
references.pmid: 19647174
references.citation: Nat Rev Cancer. 2011 May;11(5):325-37
references.pmid: 21508971
references.citation: Biochem Pharmacol. 2010 Sep 15;80(6):811-8
references.pmid: 20510678
references.citation: J Nucl Med. 2009 Nov;50(11):1820-7
references.pmid: 19837767
references.citation: Clin Cancer Res. 2012 Oct 1;18(19):5427-37
references.pmid: 22893629
references.citation: Radiology. 2011 Jun;259(3):852-61
references.pmid: 21493787
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19611-6
references.pmid: 22106302
references.citation: J Nucl Med. 2008 Jun;49 Suppl 2:43S-63S
references.pmid: 18523065
references.citation: Pharmacol Ther. 2005 Sep;107(3):271-85
references.pmid: 16112332
references.citation: J Nucl Med. 2013 Jan;54(1):117-23
references.pmid: 23232273