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Fluorinated tracers for imaging cancer with positron emission tomography

  • Olivier Couturier
  • André Luxen
  • Jean-François Chatal
  • Jean-Philippe Vuillez
  • Pierre Rigo
  • Roland HustinxEmail author
Review Article

Abstract

2-[18F]fluoro-2-deoxy-d-glucose (FDG) is currently the only fluorinated tracer used in routine clinical positron emission tomography (PET). Fluorine-18 is considered the ideal radioisotope for PET imaging owing to the low positron energy (0.64 MeV), which not only limits the dose rate to the patient but also results in a relatively short range of emission in tissue, thereby providing high-resolution images. Further, the 110-min physical half-life allows for high-yield radiosynthesis, transport from the production site to the imaging site and imaging protocols that may span hours, which permits dynamic studies and assessment of potentially fairly slow metabolic processes. The synthesis of fluorinated tracers as an alternative to FDG was initially tested using nucleophilic fluorination of the molecule, as performed when radiolabelling with iodine-124 or bromide-76. However, in addition to being long, with multiple steps, this procedure is not recommended for bioactive molecules containing reactive groups such as amine or thiol groups. Radiochemical yields are also often low. More recently, radiosynthesis from prosthetic group precursors, which allows easier radiolabelling of biomolecules, has led to the development of numerous fluorinated tracers. Given the wide availability of 18F, such tracers may well develop into important routine tracers. This article is a review of the literature concerning fluorinated radiotracers recently developed and under investigation for possible PET imaging in cancer patients. Two groups can be distinguished. The first includes “generalist” tracers, i.e. tracers amenable to use in a wide variety of tumours and indications, very similar in this respect to FDG. These are tracers for non-specific cell metabolism, such as protein synthesis, amino acid transport, nucleic acid synthesis or membrane component synthesis. The second group consists of “specific” tracers for receptor expression (i.e. oestrogens or somatostatin), cell hypoxia or bone metabolism.

Keywords

Positron emission tomography Fluorinated tracers Cancer imaging 

References

  1. 1.
    Alavi A, Reivich M. Guest editorial: the conception of FDG-PET imaging. Semin Nucl Med 2002;32:2–5.PubMedGoogle Scholar
  2. 2.
    Warburg O. The metabolism of tumors. London: Arnold Constable; 1930. p. 75–327.Google Scholar
  3. 3.
    Warburg O. On the origin of cancer cells. Science 1956;123:309–14.PubMedGoogle Scholar
  4. 4.
    Schirrmeister H, Kuhn H, Guhlmann A, et al. Immunostaging in pancreatic cancer and chronic active pancreatitis: does in vivo FDG-uptake correlate with proliferative activity? J Nucl Med 2001;42:721–5.PubMedGoogle Scholar
  5. 5.
    Kubota R, Kubota K, Yamada S, et al. Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 1992;33:1972–80.PubMedGoogle Scholar
  6. 6.
    Brown RS, Leung JY, Fisher SJ, et al. Intratumoral distribution of tritiated fluorodeoxyglucose in breast carcinoma: I. Are inflammatory cells important? J Nucl Med 1995;36:1854–61.PubMedGoogle Scholar
  7. 7.
    Higashi K, Clavo AC, Wahl RL. In vitro assessment of 2-fluoro-2-deoxy-d-glucose, l-methionine and thymidine as agents to monitor the early response of a human adenocarcinoma cell line to radiotherapy. J Nucl Med 1993;34:773–9.PubMedGoogle Scholar
  8. 8.
    Lewis P, Salama A. Uptake of fluorine-18-fluorodeoxyglucose in sarcoidosis. J Nucl Med 1994;35:1647–9.PubMedGoogle Scholar
  9. 9.
    Minn H, Clavo AC, Grenman R, et al. In vitro comparison of cell proliferation kinetics and uptake of tritiated fluorodeoxyglucose and l-methionine in squamous-cell carcinoma of the head and neck. J Nucl Med 1995;36:252–8.PubMedGoogle Scholar
  10. 10.
    Patz EF Jr, Lowe VJ, Hoffman JM, et al. Focal pulmonary abnormalities: evaluation with F-18 fluorodeoxyglucose PET scanning. Radiology 1993;188:487–90.PubMedGoogle Scholar
  11. 11.
    Johnstone RM, Scholefield PG. Amino acid transport in tumor cells. Adv Cancer Res 1965;9:143–226.PubMedGoogle Scholar
  12. 12.
    Isselbacher KJ. Sugar and amino acid transport by cells in culture—differences between normal and malignant cells. N Engl J Med 1972;286:929–33.PubMedGoogle Scholar
  13. 13.
    Bush H, Davis JR, Honig GR, et al. The uptake of a variety of amino acids into nuclear proteins of tumors and other tissues. Cancer Res 1959;19:1030–9.PubMedGoogle Scholar
  14. 14.
    Wiseman G, Ghadially FN. Studies in amino-acid uptake by RD3 sarcoma cell suspensions in vitro. Br J Cancer 1955;9:480.PubMedGoogle Scholar
  15. 15.
    Saier MH, Daniels GA, Boerner P, et al. Neutral amino acid transport systems in animal cells: potential targets of oncogene action and regulators of cellular growth. J Membr Biol 1988;104:1–20.PubMedGoogle Scholar
  16. 16.
    Souba WW, Pacitti AJ. How amino acids get into cells: mechanisms, models, menus and mediators. J Parenter Enteral Nutr 1992;16:569–78.Google Scholar
  17. 17.
    Ishiwata K, Kubota K, Murakami M, et al. Re-evaluation of amino acid PET studies: can the protein synthesis rates in brain and tumor tissues be measured in vivo? J Nucl Med 1993;34:1936–43.PubMedGoogle Scholar
  18. 18.
    Daemen BJ, Zwertbroek R, Elsinga PH, et al. PET studies with l-[1-11C]tyrosine, l-[methyl-11C]methionine and 18F-fluorodeoxyglucose in prolactinomas in relation to bromocryptine treatment. Eur J Nucl Med 1991;18:453–60.PubMedGoogle Scholar
  19. 19.
    Miyagawa G, Oku T, Uehara H, et al. Facilitated amino acid transport is upregulated in brain tumors. J Cereb Blood Flow Metab 1998;18:500–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Martarello L, McConathy J, Camp M, et al. Synthesis and biological evaluation of Syn and Anti FMACBC, new amino acids for tumor imaging with PET. J Label Compd Radiopharm 2001;44:S385–7.CrossRefGoogle Scholar
  21. 21.
    Shoup TM, Olson J, Hoffman JM, et al. Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumours. J Nucl Med 1999;40:331–8.PubMedGoogle Scholar
  22. 22.
    Uehara H, Miyagawa T, Tjuvajev J, et al. Imaging experimental brain tumors with 1-aminocyclopentane carboxylic acid and alpha-aminoisobutyric acid: comparison to fluorodeoxyglucose and diethylenetriaminepentaacetic acid in morphologically defined tumor regions. J Cereb Blood Flow Metab 1997;17:1239–53.PubMedGoogle Scholar
  23. 23.
    Kubota K, Yamada K, Yoshioka S, et al. Differential diagnosis of idiopathic fibrosis from malignant lymphadenopathy with PET and F-18 fluorodeoxyglucose. Clin Nucl Med 1992;17:361–3.PubMedGoogle Scholar
  24. 24.
    Kubota K, Matsuzawa T, Fujiwara T, et al. Differential diagnosis of AH109A tumor and inflammation by radioscintigraphy with l-[methyl-11C]methionine. Jpn J Cancer Res 1989;80:778–82.PubMedGoogle Scholar
  25. 25.
    Kubota R, Kubota K, Yamada S, et al. Methionine uptake by tumor tissue: a microautoradiographic comparison with FDG. J Nucl Med 1995;36:484–92.PubMedGoogle Scholar
  26. 26.
    Kole AC, Plaat BE, Hoekstra HJ, et al. FDG and l-[1-11C]-tyrosine imaging of soft-tissue tumors before and after therapy. J Nucl Med 1999;40:381–6.PubMedGoogle Scholar
  27. 27.
    Kuwert T, Morgenroth C, Woesler B, et al. Uptake of iodine-123-alpha-methyl tyrosine by gliomas and non-neoplastic brain lesions. Eur J Nucl Med 1996;23:1345–53.PubMedGoogle Scholar
  28. 28.
    Vaalburg W, Coenen HH, Crouzel C, et al. Amino acids for the measurement of protein synthesis in vivo by PET. Int J Radiat Appl Instrum B 1992;19:227–37.CrossRefGoogle Scholar
  29. 29.
    Coenen HH, Kling P, Stocklin G. Cerebral metabolism of l-[2-18F]fluorotyrosine, a new PET tracer of protein synthesis. J Nucl Med 1989;30:1367–72.PubMedGoogle Scholar
  30. 30.
    Lemaire C, Gillet S, Kameda M. Enantioselective synthesis of 2-[18F]fluoro-l-tyrosine by catalytic phase-transfer alkylation. J Label Compd Radiopharm 2001;44:S857–9.Google Scholar
  31. 31.
    Wienhard K, Herholz K, Coenen HH, et al. Increased amino acid transport into brain tumors measured by PET of l-(2-18F)fluorotyrosine [see comments]. J Nucl Med 1991;32:1338–46.PubMedGoogle Scholar
  32. 32.
    Saier MH Jr. A functional-phylogenetic system for the classification of transport proteins. J Cell Biochem 1999;Suppl 33–34:84–94.Google Scholar
  33. 33.
    Daemen BJ, Elsinga PH, Ishiwata K, et al. A comparative PET study using different 11C-labelled amino acids in Walker 256 carcinosarcoma-bearing rats. Int J Rad Appl Instrum B 1991;18:197–204.CrossRefPubMedGoogle Scholar
  34. 34.
    Ishiwata K, Kubota K, Murakami M, et al. A comparative study on protein incorporation of l-[methyl-3H]methionine, l-[1-14C]leucine and l-2-[18F]fluorotyrosine in tumor bearing mice. Nucl Med Biol 1993;20:895–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Hustinx R, Lemaire C, Jerusalem G, et al. Whole-body tumor imaging using PET and 2-18F-fluoro-l-tyrosine: preliminary evaluation and comparison with 18F-FDG. J Nucl Med 2003;44:533–9.PubMedGoogle Scholar
  36. 36.
    Tomiyoshi K, Amed K, Muhammad S, et al. Synthesis of isomers of 18F-labelled amino acid radiopharmaceutical: position 2- and 3-l-18F-alpha-methyltyrosine using a separation and purification system. Nucl Med Commun 1997;18:169–75.PubMedGoogle Scholar
  37. 37.
    Amano S, Inoue T, Tomiyoshi K, et al. In vivo comparison of PET and SPECT radiopharmaceuticals in detecting breast cancer. J Nucl Med 1998;39:1424–7.PubMedGoogle Scholar
  38. 38.
    Inoue T, Tomiyoshi K, Higuichi T, et al. Biodistribution studies on l-3-[fluorine-18]fluoro-alpha-methyl tyrosine: a potential tumor-detecting agent. J Nucl Med 1998;39:663–7.PubMedGoogle Scholar
  39. 39.
    Langen KJ, Roosen N, Coenen HH, et al. Brain tumor uptake of l-3-[123I]iodo-alpha-methyl tyrosine: competition with natural l-amino acids [see comments]. J Nucl Med 1991;32:1225–9.PubMedGoogle Scholar
  40. 40.
    Lahoutte T, Caveliers V, Dierickx L, et al. In vitro characterization of the influx of 3-[125I]iodo-l-alpha-methyltyrosine and 2-[125I]iodo-l-tyrosine into U266 human myeloma cells: evidence for system T transport. Nucl Med Biol 2001;28:129–34.CrossRefPubMedGoogle Scholar
  41. 41.
    Lahoutte T, Caveliers V, Franken PR, et al. Increased tumor uptake of 3-123I-Iodo-l-alpha-methyltyrosine after preloading with amino acids: an in vivo animal imaging study. J Nucl Med 2002;43:1201–6.PubMedGoogle Scholar
  42. 42.
    Lahoutte T, Mertens J, Caveliers V, et al. Comparative biodistribution of iodinated amino acids in rats: selection of the optimal analog for oncologic imaging outside the brain. J Nucl Med 2003;44:1489–94.PubMedGoogle Scholar
  43. 43.
    Watanabe H, Inoue T, Shinozaki T, et al. PET imaging of musculoskeletal tumours with fluorine-18-methyltyrosine: comparison with fluorine-18 fluorodeoxyglucose PET. Eur J Nucl Med 2000;27:1509–17.CrossRefPubMedGoogle Scholar
  44. 44.
    Schluter B, Bohuslavizki KH, Beyer W, et al. Impact of FDG PET on patients with differentiated thyroid cancer who present with elevated thyroglobulin and negative 131I scan. J Nucl Med 2001;42:71–6.PubMedGoogle Scholar
  45. 45.
    Dehdashti F, Siegel BA, Griffeth LK, et al. Benign versus malignant intraosseous lesions: discrimination by means of PET with 2-[F-18]fluoro-2-deoxy-d-glucose. Radiology 1996;200:243–7.PubMedGoogle Scholar
  46. 46.
    Inoue T, Koyama K, Oriuchi N, et al. Detection of malignant tumors: whole-body PET with fluorine 18 alpha-methyl tyrosine versus FDG-preliminary study. Radiology 2001;220:54–62.PubMedGoogle Scholar
  47. 47.
    Wester HJ, Herz M, Weber W, et al. Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-l-tyrosine for tumor imaging. J Nucl Med 1999;40:205–12.PubMedGoogle Scholar
  48. 48.
    Heiss P, Mayer S, Herz M, et al. Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-l-tyrosine in vitro and in vivo. J Nucl Med 1999;40:1367–73.PubMedGoogle Scholar
  49. 49.
    Weber WA, Ott K, Becker K, et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 2001;19:3058–65.PubMedGoogle Scholar
  50. 50.
    Rau FC, Weber WA, Wester HJ, et al. O-(2-[18F]fluoroethyl)-l-tyrosine (FET): a tracer for differentiation of tumour from inflammation in murine lymph nodes. Eur J Nucl Med 2002;29:1039–46.CrossRefGoogle Scholar
  51. 51.
    Schreckenberger M, Kadalie C, Enk A, et al. First results of F-18-fluoroethyl-tyrosine PET for imaging of metastatic malignant melanoma. J Nucl Med 2001;42:30P.Google Scholar
  52. 52.
    Weber WA, Wester HJ, Grosu AL, et al. O-(2-[18F]fluoroethyl)-l-tyrosine and l-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study. Eur J Nucl Med 2000;27:542–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Ishiwata K, Ido T, Takahashi T, et al. Feasibility study of fluorine-18 labeled dopa for melanoma imaging. Int J Rad Appl Instrum B 1989;16:371–4.CrossRefPubMedGoogle Scholar
  54. 54.
    Luxen A, Perlmutter M, Bida GT, et al. Remote, semiautomated production of 6-[18F]fluoro-l-dopa for human studies with PET. Int J Rad Appl Instrum A 1990;41:275–81.CrossRefPubMedGoogle Scholar
  55. 55.
    Ishiwata K, Kubota K, Kubota R, et al. Selective 2-[18F]fluorodopa uptake for melanogenesis in murine metastatic melanomas. J Nucl Med 1991;32:95–101.PubMedGoogle Scholar
  56. 56.
    Kubota R, Yamada S, Ishiwata K, et al. Active melanogenesis in non-S phase melanocytes in B16 melanomas in vivo investigated by double-tracer microautoradiography with 18F- fluorodopa and 3H-thymidine. Br J Cancer 1992;66:614–8.PubMedGoogle Scholar
  57. 57.
    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.PubMedGoogle Scholar
  58. 58.
    Graham MM. Combined 18F-FDG-FDOPA tumor imaging for assessing response to therapy. J Nucl Med 2001;42:257–8.PubMedGoogle Scholar
  59. 59.
    Hoegerle S, Altehoefer C, Ghanem N, et al. Whole-body 18F dopa PET for detection of gastrointestinal carcinoid tumors. Radiology 2001;220:373–80.PubMedGoogle Scholar
  60. 60.
    Hoegerle S, Altehoefer C, Ghanem N, et al. 18F-DOPA positron emission tomography for tumour detection in patients with medullary thyroid carcinoma and elevated calcitonin levels. Eur J Nucl Med 2001;28:64–71.CrossRefPubMedGoogle Scholar
  61. 61.
    Becherer A, Karanikas G, Szabo M, et al. Brain tumour imaging with PET: a comparison between [18F]fluorodopa and [11C]methionine. Eur J Nucl Med Mol Imaging 2003;30:1561–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Jacob T, Grahek D, Younsi N, et al. Positron emission tomography with [18F]FDOPA and [18F]FDG in the imaging of small cell lung carcinoma: preliminary results. Eur J Nucl Med Mol Imaging 2003;30:1266–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Krenning EP, Bakker WH, Kooij PPM, et al. Somatostatin receptor scintigraphy with indium-111-DTPA-d-Phe-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide. J Nucl Med 1992;33:652–8.PubMedGoogle Scholar
  64. 64.
    Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993;20:716–31.PubMedGoogle Scholar
  65. 65.
    Krenning EP, Kwekkeboom DJ, Oei HY, et al. Somatostatin-receptor scintigraphy in gastroenteropancreatic tumors. An overview of European results. Ann N Y Acad Sci 1994;733:416–24.PubMedGoogle Scholar
  66. 66.
    Reubi JC, Krenning EP, Lamberts SWJ, et al. In vitro detection of somatostatin receptors in human tumours. Metabolism 1992;41(9):104–10.Google Scholar
  67. 67.
    Reubi JC, Laissue J, Krenning EP, et al. Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implication. J Steroid Biochem Mol Biol 1992;43:27–35.CrossRefPubMedGoogle Scholar
  68. 68.
    Pearse AGE, Polak JM, Health CM. Polypeptide hormone production by carcinoid apudomas and their relevant cytochemistry. Virchows Arch [B] 1974;16:95–109.Google Scholar
  69. 69.
    Reubi JC, Maurer R, Klijn JG, et al. High incidence of somatostatin receptors in human meningiomas: biochemical characterization. J Clin Endocrinol Metab 1986;63:433–8.PubMedGoogle Scholar
  70. 70.
    Reubi JC, Lang W, Maurer R, et al. Distribution and biochemical characterization of somatostatin receptors in tumours of the human central nervous system. Cancer Res 1987;47:5758–65.PubMedGoogle Scholar
  71. 71.
    Kwekkeboom DJ, Reubi JC, Lamberts SWJ, et al. In vivo somatostatin receptor imaging in medullary thyroid carcinoma. J Clin Endocrinol Metab 1993;76:1413–17.CrossRefPubMedGoogle Scholar
  72. 72.
    Reubi JC, Waser B, Sheppard M, et al. Somatostatin receptors are present in small-cell but not in non-small-cell primary lung carcinomas: relationship to EGF receptors. Int J Cancer 1990;45:269–74.PubMedGoogle Scholar
  73. 73.
    Reubi JC, Waser B, Vanhagen M, et al. In vitro and in vivo detection of somatostatin receptors in human malignant lymphomas. Int J Cancer 1992;50:895–900.PubMedGoogle Scholar
  74. 74.
    Reubi JC, Horisberger U, Waser B, et al. Preferential location of somatostatin receptors in germinal centers of human gut lymphoid tissue. Gastroenterology 1992;103:1207–14.PubMedGoogle Scholar
  75. 75.
    Goldshmith SJ, Macapinlac HA, O’Brien JP. Somatostatin receptor imaging in lymphoma. Semin Nucl Med 1995;25:262–71.PubMedGoogle Scholar
  76. 76.
    Reubi JC, Schaer JC, Waser B, et al. Affinity profiles for human somatostatin receptor sst1–sst5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 2000;27:273–82.CrossRefPubMedGoogle Scholar
  77. 77.
    Kvols LK, Reubi J-C, Horisberger U, et al. The presence of somatostatin receptors in malignant neuroendocrine tumor tissue predicts reponsiveness to octreotide. Yale J Biol Med 1992;65:505–18.PubMedGoogle Scholar
  78. 78.
    Bakker WH, Krenning EP, Breeman WAP, et al. Receptor scintigraphy with radioiodined somatostatin analogue: radiolabeling, purification, biologic activity and in vivo application in animals. J Nucl Med 1990;31:1501–9.PubMedGoogle Scholar
  79. 79.
    Bakker WH, Albert A, Bruns C, et al. [111In-DTPA-d-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation. Life Sci 1991;49:1583–91.CrossRefPubMedGoogle Scholar
  80. 80.
    Maina T, Stolz B, Albert R, et al. Synthesis, radiochemical and biological evaluation of 99mTc[N4-(d)-Phe1]octreotide, a new derivative with high affinity for somatostatin receptors. In: Nicolini M, Bandoli G, Mazzi U, editors. Technetium and rhenium in chemistry and nuclear medicine.New York: Cortina International, Raven; 1995. p. 395–400.Google Scholar
  81. 81.
    Maina T, Stolz B, Albert R, et al. Synthesis, radiochemistry and biological evaluation of a new somatostatin analogue (SZ 219-387) labelled with technetium 99m. Eur J Nucl Med 1994;21:437–44.PubMedGoogle Scholar
  82. 82.
    Gabriel M, Decristoforo C, Donnemiller E, et al. An intrapatient comparison of 99mTc-EDDA/HYNIC-TOC with 111In-DTPA-octreotide for diagnosis of somatostatin receptor-expressing tumors. J Nucl Med 2003;44:708–16.PubMedGoogle Scholar
  83. 83.
    Lamberts SWJ, Krenning EP, Reubi J-C. The role of somatostatin and its analogs in the diagnosis and treatment of tumours. Endocr Rev 1991;12:450–82.PubMedGoogle Scholar
  84. 84.
    Anderson JH, Dehdashti F, Cutler PD, et al. 64Cu-TETA-octreotide as a PET imaging agent for patients with neuroendocrine tumours. J Nucl Med 2001;42:213–21.PubMedGoogle Scholar
  85. 85.
    Ugur O, Kothari PJ, Finn RD, et al. Ga-66 labelled somatostatin analogue DOTA-d-Phe1-Tyr3-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumours. Nucl Med Biol 2002;29:147–57.CrossRefPubMedGoogle Scholar
  86. 86.
    Hofmann M, Maecke H, Borner R, et al. Biokinetics an imaging with the somatostatin receptor PET radioligand 68Ga-DOTATOC: preliminary data. Eur J Nucl Med 2001;28:1751–7.CrossRefPubMedGoogle Scholar
  87. 87.
    Jamar F, Barone R, Mathieu I, et al. 86Y-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (SMT487)—a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion. Eur J Nucl Med Mol Imaging 2003;30:510-8.Google Scholar
  88. 88.
    Guhlke S, Wester HJ, Bruns C, et al. 2-[18F]fluoropropionyl-d-Phe1-octreotide, a potential radiopharmaceutical for quantitative somatostatin receptor imaging with PET: synthesis, radiolabeling, in vitro validation and biodistribution in mice. Nucl Med Biol 1994;21:819–25.CrossRefPubMedGoogle Scholar
  89. 89.
    Wester HJ, Brockmann J, Rosch F, et al. PET-pharmacokinetics of 18F-octreotide: a comparison with 67Ga-DFO- and 86Y-DTPA-octreotide. Nucl Med Biol 1997;24:275–86.CrossRefPubMedGoogle Scholar
  90. 90.
    Schottelius M, Wester HJ, Reubi JC, et al. Improvement of pharmacokinetics of radioiodinated Tyr(3)-octreotide by conjugation with carbohydrates. Bioconjug Chem 2002;13:1021–30.CrossRefPubMedGoogle Scholar
  91. 91.
    Wester HJ, Schottelius M, Scheidhauer K, et al. Comparison of radioiodinated TOC, TOCA and Mtr-TOCA: the effect of carbohydration on the pharmacokinetics. Eur J Nucl Med Mol Imaging 2002;29:28–38.CrossRefPubMedGoogle Scholar
  92. 92.
    Wester HJ, Schottelius M, Scheidhauer K, et al. PET imaging of somatostatin receptors: design, synthesis and preclinical evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide. Eur J Nucl Med Mol Imaging 2003;30:117–22.CrossRefPubMedGoogle Scholar
  93. 93.
    Kong X, Zhu Q, Vidal P, et al. Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3′-fluoro-3′-deoxythymidine and 3′-azido-3′-deoxythymidine. Antimicrob Agents Chemother 1992;36:808–18.PubMedGoogle Scholar
  94. 94.
    Wilson I, Chatterjee S, Wolf W. The use of 3′-fluoro-3′-deoxythymidine and studies of its 18F-radiolabeling, as a tracer for the non-invasive monitoring of the biodistribution of drugs against AIDS. J Fluorine Chem 1991;55:283–9.CrossRefGoogle Scholar
  95. 95.
    Grierson J, Shields A, Eary J. Development of a radiosynthesis for 3′-[18F]fluoro-3′-deoxynucleosides. J Label Compd Radiopharm 1997;10:60–2.Google Scholar
  96. 96.
    Grierson J, Shields A. Radiosynthesis of 3′-deoxy-3′-[18F]fluorothymidine: [18F]FLT for imaging of cellular proliferation in vivo. Nucl Med Biol 2000;27:143–56.CrossRefPubMedGoogle Scholar
  97. 97.
    Machulla H, Blocher A, Kuntzsch M, et al. Simplified labeling approach for synthesizing 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT). J Radioanal Nucl Chem 2000;243:843–6.CrossRefGoogle Scholar
  98. 98.
    Wodarski C, Eisenbarth J, Weber K, et al. Synthesis of 3′-deoxy-3′-[18F]fluoro-thymidine with 2,3′-O-anhydro-5′-O-(4,4′-dimethoxytrityl)thymidine. J Label Compd Radiopharm 2000;43:1211–8.CrossRefGoogle Scholar
  99. 99.
    Martin S, Eisenbarth J, Wagner-Utermann U, et al. [18F]FLT: 18F labeling of 3-Boc-1-(2-deoxy-3-O-nosyl-5-O-trityl-b-d-lyxofuranosyl)thymine and other thymine derivatives. J Nucl Med 2000;41:255P.Google Scholar
  100. 100.
    Martin S, Eisenbarth J, Wagner-Utermann U, et al. A new precursor for the radiosynthesis of [18F]FLT. Nucl Med Biol 2002;29:263–73.CrossRefPubMedGoogle Scholar
  101. 101.
    Belt J, Marina N, Phelps D, et al. Nucleoside transport in normal and neoplastic cells. Adv Enzyme Regul 1993;33:235–52.CrossRefPubMedGoogle Scholar
  102. 102.
    Coppock D, Pardee A. Control of thymidine kinase mRNA during the cell cycle. Mol Cell Biol 1987;7:2925–32.PubMedGoogle Scholar
  103. 103.
    Gross M, Merrill G. Regulation of thymidine kinase protein levels during myogenic withdrawal from the cell cycle is independent of mRNA regulation. Nucl Acids Res 1988;16:11625–43.PubMedGoogle Scholar
  104. 104.
    Sherley J, Kelly T. Regulation of human thymidine kinase during the cell cycle. J Biol Chem 1988;263:8350–8.PubMedGoogle Scholar
  105. 105.
    Ito M, Conrad S. Independent regulation of thymidine kinase mRNA and enzyme levels in serum-stimulated cells. J Biol Chem 1990;265:6954–60.PubMedGoogle Scholar
  106. 106.
    Bartrek J, Bartkova J, Lukas J. The retinoblastoma protein pathway and the restriction point. Curr Opin Cell Biol 1996;8:805–14.CrossRefPubMedGoogle Scholar
  107. 107.
    Ewen M. The cell cycle and the retinoblastoma protein family. Cancer Metastasis Rev 1994;13:45–66.PubMedGoogle Scholar
  108. 108.
    Sherr CD. Type cyclins. Trends Biol Sci 1995;20:187–90.CrossRefGoogle Scholar
  109. 109.
    Sherr C, Roberts J. Inhibitors of mammalian G1 cycline-dependent kinases. Genes Dev 1995;9:1149–63.PubMedGoogle Scholar
  110. 110.
    Weinberg R. The retinoblastoma protein and cell cycle control. Cell 1995;81:323–30.PubMedGoogle Scholar
  111. 111.
    Hengstschlager M, Knofler M, Mullner E, et al. Different regulation of thymidine kinase during the cell cycle of normal versus DNA tumor virus-transformed cells. J Biol Chem 1994;269:13836–42.PubMedGoogle Scholar
  112. 112.
    Hengstschlager M, Oliver P, Hengstshlager-Ottnad E, et al. Loss of the p16/MTS1 tumor suppressor gene causes E2F-mediated deregulation of essential enzymes of the DNA precursor metabolism. DNA Cell Biol 1996;15:41–51.PubMedGoogle Scholar
  113. 113.
    Hengstschlager M, Hengstshlager-Ottnad E, Oliver P, et al. The role of p16 in the E2F-dependent thymidine kinase regulation. Oncogene 1996;12:1635–43.PubMedGoogle Scholar
  114. 114.
    Toyohara J, Waki A, Takamatsu S, et al. Basis of FLT as cell proliferattion marker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol 2002;29:281–7.CrossRefPubMedGoogle Scholar
  115. 115.
    Shields A, Grierson J, Dohmen B, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 1998;4:1334–6.CrossRefPubMedGoogle Scholar
  116. 116.
    Eriksson S, Kierdaszuk B, Mucnh-Peterson B, et al. Comparison of the substate specificities of human thymidiine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogs. Biochem Biophys Res Commun 1991;176:586–92.PubMedGoogle Scholar
  117. 117.
    Nottebrock H, Then R. Thymidine concentrations in serum and urine of different animal species and man. Biochem Pharmacol 1977;26:2175–9.CrossRefPubMedGoogle Scholar
  118. 118.
    Mier W, Haberkorn U, Eisenhut M. [18F]FLT; portrait of a proliferation marker. Eur J Nucl Med Mol Imaging 2002;29:165–9.CrossRefPubMedGoogle Scholar
  119. 119.
    Wagner M, Seitz U, Buck A, et al. 3′-[18F]fluoro-3′-deoxythymidine ([18F]-FLT) as positron emission tomography tracer for imaging proliferation in a murine B-cell lymphoma model and in the human disease. Cancer Res 2003;63:2681–7.PubMedGoogle Scholar
  120. 120.
    Seitz U, Wagner M, Neumaier B, et al. Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) in pancreatic cancer cell lines. Eur J Nucl Med Mol Imaging 2002;29:1174–81.CrossRefPubMedGoogle Scholar
  121. 121.
    Vesselle H, Grierson J, Peterson LM, et al. 18F-fluorothymidine radiation dosimetry in human PET imaging studies. J Nucl Med 2003;44:1482–8.PubMedGoogle Scholar
  122. 122.
    Buck AK, Schirrmeister H, Hetzel M, et al. 3-Deoxy-3-[18]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Cancer Res 2002;62:3331–4.PubMedGoogle Scholar
  123. 123.
    Buck AK, Halter G, Schirrmeister H, et al. Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. J Nucl Med 2003;44:1426–31.PubMedGoogle Scholar
  124. 124.
    Dittmann H, Dohmen BM, Paulsen F, et al. [18F]FLT PET for diagnosis and staging of thoracic tumours. Eur J Nucl Med Mol Imaging 2003;30:1407–12.CrossRefPubMedGoogle Scholar
  125. 125.
    Francis DL, Visvikis D, Costa DC, et al. Potential impact of [18F]3′-deoxy-3′-fluorothymidine versus [18F]fluoro-2-deoxy-d-glucose in positron emission tomography for colorectal cancer. Eur J Nucl Med Mol Imaging 2003;30:988–94.CrossRefPubMedGoogle Scholar
  126. 126.
    Francis DL, Freeman A, Visvikis D, et al. In vivo imaging of cellular proliferation in colorectal cancer using positron emission tomography. Gut 2003;52:1602–6.CrossRefPubMedGoogle Scholar
  127. 127.
    Barthel H, Cleij MC, Collingridge DR, et al. 3′-deoxy-3′-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 2003;63:3791–8.PubMedGoogle Scholar
  128. 128.
    Dittmann H, Dohmen BM, Kehlbach R, et al. Early changes in [18F]FLT uptake after chemotherapy: an experimental study. Eur J Nucl Med Mol Imaging 2002;29:1462–9.CrossRefPubMedGoogle Scholar
  129. 129.
    Shields AF, Dohmen BM, Mangner TJ, et al. Use of F-18-FLT for imaging gastrointestinal tumors. J Nucl Med 2001;42:108.Google Scholar
  130. 130.
    Carter EA, McKuster K, Syed S, et al. Comparison of (FLT)-F-18 with (18)FDG for differentiation between tumor and focal sites of infection in rats. J Nucl Med 2002;43:1074.Google Scholar
  131. 131.
    Wald LL, Nelson SJ, Day MR, et al. Serial proton magnetic resonance spectroscopy imaging of glioblastoma multiforme after brachytherapy. J Neurosurg 1997;87:525–34.PubMedGoogle Scholar
  132. 132.
    Tedeschi G, Lundbom N, Raman R, et al. Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study. J Neurosurg 1997;87:516–24.PubMedGoogle Scholar
  133. 133.
    Hara T. 18F-fluorocholine: a new oncologic PET tracer. J Nucl Med 2001;42:1815–6.PubMedGoogle Scholar
  134. 134.
    Hara T, Kosaka N, Kondo T, et al. Imaging of brain tumor, lung cancer, esophagus cancer, colon cancer, prostate cancer, and bladder cancer with (11C)choline. J Nucl Med 1997;38(Suppl):250P.Google Scholar
  135. 135.
    Hara T, Kosaka N, Shinoura N, et al. PET imaging of brain tumor with [methyl-11C]choline. J Nucl Med 1997;38:842–7.PubMedGoogle Scholar
  136. 136.
    Hara T, Inagaki K, Kosaka N, et al. Sensitive detection of mediastinal lymph nodes metastasis of lung cancer with 11C-choline PET. J Nucl Med 2000;41:1507–13.PubMedGoogle Scholar
  137. 137.
    Kobori O, Kirihara N, Kosaka N, et al. Positron emission tomography of esophagal carcinoma using 11C-choline and 18F-fluorodeoxyglucose. Cancer 1999;1999:1638–48.CrossRefGoogle Scholar
  138. 138.
    Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11-choline. J Nucl Med 1998;39:990–5.PubMedGoogle Scholar
  139. 139.
    Hara T, Yuasa M. Automated synthesis of fluorine-18 labeled choline analog: 2-fluoroethyl-dimethyl-2-oxyethylammonium. J Nucl Med 1997;38(Suppl):44P.Google Scholar
  140. 140.
    DeGrado TR, Coleman RE, Wang S, et al. Synthesis and evaluation of 18F-labeled choline as an oncologic tracer for positron emission tomography: initial findings in prostate cancer. Cancer Res 2000;61:110–7.Google Scholar
  141. 141.
    DeGrado TR, Baldwin SW, Wang S, et al. Synthesis and evaluation of 18F-labeled choline analogs as oncologic PET tracers. J Nucl Med 2001;42:1805–14.PubMedGoogle Scholar
  142. 142.
    DeGrado TR, Reiman RE, Price DT, et al. Pharmacokinetics and radiation dosimetry of 18F-fluorocholine. J Nucl Med 2002;43:92–6.PubMedGoogle Scholar
  143. 143.
    Hara T. 11C-choline and 2-deoxy-2-[18F]fluoro-d-glucose in tumor imaging with positron emission tomography. Mol Imaging Biol 2002;4:267–73.CrossRefPubMedGoogle Scholar
  144. 144.
    Hara T, Kosaka N, Kishi H. Development of 18F-fluoroethylcholine for cancer imaging with PET: synthesis, biochemistry, and prostate cancer imaging. J Nucl Med 2002;43:187–99.PubMedGoogle Scholar
  145. 145.
    Price DT, Coleman RE, Liao RP, et al. Comparison of [18F]fluorocholine and [18F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol 2002;168:273–80.CrossRefPubMedGoogle Scholar
  146. 146.
    Yorek MA, Dunlap JA, Spector AA, et al. Effect of ethanolamine on choline uptake and incorporation into phosphatidylcholine in human Y79 retinoblatoma cells. J Lipid Res 1986;27:1205–13.PubMedGoogle Scholar
  147. 147.
    Rosen MA, Jones RM, Yano Y, et al. Carbon-11 choline: synthesis, purification, and brain uptake inhibition by 2-dimethylaminoethanol. J Nucl Med 1985;26:1424–8.PubMedGoogle Scholar
  148. 148.
    Wyss MT, Weber B, Honer M, et al. 18F-choline in experimental soft tissue infection assessed with autoradiography and high-resolution PET. Eur J Nucl Med Mol Imaging 2004;31:312–6.CrossRefPubMedGoogle Scholar
  149. 149.
    Kiesewetter DO, Kilbourn MR, Landvatter SW, et al. Preparation of four fluorine- 18-labeled estrogens and their selective uptakes in target tissues of immature rats. J Nucl Med 1984;25:1212–21.PubMedGoogle Scholar
  150. 150.
    Jonson SD, Bonasera TA, Dehdashti F, et al. Comparative breast tumor imaging and comparative in vitro metabolism of 16α-[18F]fluoroestradiol-17β and 16β-[18F]fluoromoxestrol in isolated hepatocytes. Nucl Med Biol 1999;26:123–30.CrossRefPubMedGoogle Scholar
  151. 151.
    Brandes SJ, Katzenellenbogen JA. Fluorinated androgens and progestins: molecular probes for androgen and progesterone receptors with potential use in positron emission tomography. Mol Pharmacol 1987;32:391–403.PubMedGoogle Scholar
  152. 152.
    Liu A, Carlson KE, Katzenellenbogen JA. Synthesis of high affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography. J Med Chem 1992;35:2113–29.PubMedGoogle Scholar
  153. 153.
    Noé G, Cheng YC, Dabiké M, et al. Tissue uptake of human sex hormone-binding globuline an its influence on ligand kinetics in the adult female rat. Biol Reprod 1992;47:970–6.PubMedGoogle Scholar
  154. 154.
    Seimbille Y, Rousseau J, Benard F, et al. 18F-labeled difluoroestradiols: preparation and preclinical evaluation as estrogen receptor-binding radiopharmaceuticals. Steroids 2002;67:765–75.CrossRefPubMedGoogle Scholar
  155. 155.
    Romer J, Fuchtner F, Steinbach J, et al. Automated production of 16α-[18F]fluoroestradiol for breast cancer imaging. Nucl Med Biol 1999;26:473–9.CrossRefPubMedGoogle Scholar
  156. 156.
    Mathias CJ, Welch MJ, Katzenellenbogen JA, et al. Characterization of the uptake of 16 α-([18F]fluoro)-17 β-estradiol in DMBA-induced mammary tumors. Int J Rad Appl Instrum B 1987;14(1):15–25.Google Scholar
  157. 157.
    Mankoff DA, Tewson TJ, Eary JF. Analysis of blood clearance and labeled metabolites for the estrogen receptor tracer [F-18]-16α-fluoroestradiol (FES). Nucl Med Biol 1997;24:341–8.CrossRefPubMedGoogle Scholar
  158. 158.
    Tewson TJ, Mankoff DA, Peterson LM, et al. Interactions of 16α-[18F]-fluoroestradiol (FES) with sex steroid binding protein (SBP). Nucl Med Biol 1999;26:905–13.CrossRefPubMedGoogle Scholar
  159. 159.
    Pomper MG, VanBrocklin H, Thieme AM, et al. 11β-Methoxy-, 11β-ethyl- and 17α-ethynyl-substitued 16α-fluoroestradiols: receptor-based imaging agents with enhanced uptake efficiency and selectivity. J Med Chem 1990;33:3143–55.PubMedGoogle Scholar
  160. 160.
    Mintun MA, Welch MJ, Siegel BA, et al. Breast cancer: PET imaging of estrogen receptors. Radiology 1988;169:45–8.PubMedGoogle Scholar
  161. 161.
    Dehdashti F, Mortimer JE, Siegel BA, et al. Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays. J Nucl Med 1995;36:1766–74.PubMedGoogle Scholar
  162. 162.
    Katzenellenbogen JA, Mathias CJ, VanBrocklin HF, et al. Titration of the in vivo uptake of 16α-[18F]fluoroestradiol by target tissues in the rat: competition by tamoxifen, and implications for quantitating estrogen receptors in vivo and the use of animal models in receptor-binding radiopharmaceutical development. Nucl Med Biol 1993;20:735–45.CrossRefPubMedGoogle Scholar
  163. 163.
    McGuire AH, Dehdashti F, Siegel BA, et al. Positron tomographic assessment of 16α-[18F] fluoro-17β-estradiol uptake in metastatic breast carcinoma. J Nucl Med 1991;32:1526–31.PubMedGoogle Scholar
  164. 164.
    Flanagan FL, Dehdashti F, Siegel BA. PET in breast cancer. Semin Nucl Med 1998;28:290–302.PubMedGoogle Scholar
  165. 165.
    Dehdashti F, Flanagan FL, Mortimer JE, et al. Positron emission tomographic assessment of “metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy. Eur J Nucl Med 1999;26:51–6.CrossRefPubMedGoogle Scholar
  166. 166.
    Romer J, Fuchtner F, Steinbach J, et al. Automated synthesis of 16α-[18F]fluoroestradiol-3,17β-disulphamate. Appl Radiat Isot 2001;55:631–9.CrossRefPubMedGoogle Scholar
  167. 167.
    Lim JL, Zheng L, Berridge MS, et al. The use of 3-methoxymethyl-16β, 17β-epiestriol-O-cyclic sulfone as the precursor in the synthesis of F-18 16α-fluoroestradiol. Nucl Med Biol 1996;23:911–5.CrossRefPubMedGoogle Scholar
  168. 168.
    Rodig H, Brust P, Romer J, et al. Distribution of estrone sulfatase in rat brain determined by in vitro autoradiography with 16α-[18F]fluoroestradiol-3,17β-disulfamate. Appl Radiat Isot 2002;56:773–80.CrossRefPubMedGoogle Scholar
  169. 169.
    Brust P, Rodig H, Romer J, et al. Distribution of 16α-[18F]fluoro-estradiol-3,17β-disulfamate in rats, tumour-bearing mice and piglets. Appl Radiat Isot 2002;57:687–95.CrossRefPubMedGoogle Scholar
  170. 170.
    Pomper MG, Katzenellenbogen JA, Welch MJ, et al. 21-[18F]fluoro-16 α-ethyl-19-norprogesterone: synthesis and target tissue selective uptake of a progestin receptor based radiotracer for positron emission tomography. J Med Chem 1988;31:1360–3.PubMedGoogle Scholar
  171. 171.
    Verhagen A, Luurtsema G, Pesser JW, et al. Preclinical evaluation of a positron emitting progestin ([18F]fluoro-16 α-methyl-19-norprogesterone) for imaging progesterone receptor positive tumours with positron emission tomography. Cancer Lett 1991;59:125–32.CrossRefPubMedGoogle Scholar
  172. 172.
    Verhagen A, Luurtsema G, Pesser JW, et al. Preclinical evaluation of a positron emitting progestin ([18F]fluoro-16 α-methyl-19-norprogesterone) for imaging progesterone receptor positive tumours with positron emission tomography. Cancer Lett 1991;59:125–32.CrossRefPubMedGoogle Scholar
  173. 173.
    Pomper MG, Katzenellenbogen JA, Welch MJ, et al. 21-[18F]fluoro-16 α-ethyl-19-norprogesterone: synthesis and target tissue selective uptake of a progestin receptor based radiotracer for positron emission tomography. J Med Chem 1988;31:1360–3.PubMedGoogle Scholar
  174. 174.
    Verhagen A, Elsinga PH, de Groot TJ, et al. A fluorine-18 labeled progestin as an imaging agent for progestin receptor positive tumors with positron emission tomography. Cancer Res 1991;51:1930–3.PubMedGoogle Scholar
  175. 175.
    Dehdashti F, McGuire AH, Van Brocklin HF, et al. Assessment of 21-[18F]fluoro-16 α-ethyl-19-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas. J Nucl Med 1991;32:1532–7.PubMedGoogle Scholar
  176. 176.
    Verhagen A, Studeny M, Luurtsema G, et al. Metabolism of a [18F]fluorine labeled progestin (21-[18F]fluoro-16 α-ethyl-19-norprogesterone) in humans: a clue for future investigations. Nucl Med Biol 1994;21:941–52.CrossRefPubMedGoogle Scholar
  177. 177.
    Choe YS, Bonasera TA, Chi DY, et al. 6[α]-[18F]fluoroprogesterone: synthesis via halofluorination-oxidation, receptor binding and tissue distribution. Nucl Med Biol 1995;22:635–42.CrossRefPubMedGoogle Scholar
  178. 178.
    Kochanny MJ, VanBrocklin HF, Kym PR, et al. Fluorine-18-labeled progestin ketals: synthesis and target tissue uptake selectivity of potential imaging agents for receptor-positive breast tumors. J Med Chem 1993;36:1120–7.PubMedGoogle Scholar
  179. 179.
    Kym PR, Carlson KE, Katzenellenbogen JA. Progestin 16α, 17α-dioxolane ketals as molecular probes for the progesterone receptor: synthesis, binding affinity, and photochemical evaluation. J Med Chem 1993;36:1111–9.PubMedGoogle Scholar
  180. 180.
    Buckman BO, Bonasera TA, Kirschbaum KS, et al. Fluorine-18-labeled progestin 16α, 17α-dioxolanes: development of high-affinity ligands for the progesterone receptor with high in vivo target site selectivity. J Med Chem 1995;38:328–37.PubMedGoogle Scholar
  181. 181.
    Liu AJ, Katzenellenbogen JA, VanBrocklin HF, et al. 20-[18F]fluoromibolerone, a positron-emitting radiotracer for androgen receptors: synthesis and tissue distribution studies. J Nucl Med 1991;32:81–8.CrossRefPubMedGoogle Scholar
  182. 182.
    Pertschuk LP, Rosenthal HE, Macchia RJ. Correlation of histochemical an biochemical analysis of androgen binding in prostatic cancer: relation to therapeutic cancer. Cancer 1982;49:984–93.PubMedGoogle Scholar
  183. 183.
    Mobbs BG, Johnson IE. Basal and estrogen-stimulated hormone receptor profiles in four R3327 rat prostatic carcinoma sublines in relation to histopathology and androgen sensitivity. Cancer Res 1988;48:3077–83.PubMedGoogle Scholar
  184. 184.
    Ekman P, Snochowski M, Dahlberg E, et al. Steroid receptors in metastatic carcinoma of the human prostate. Eur J Cancer 1979;15:257–62.CrossRefPubMedGoogle Scholar
  185. 185.
    Blankestein MA, Bolt-de-Vries J, van Aubel OGJM, et al. Hormone receptors in human prostate cancer. Scand. J Urol Nephrol 1988;Suppl 10:39–45.Google Scholar
  186. 186.
    Liu AJ, Dence CS, Welch MJ, et al. Fluorine-18-labeled androgens: radiochemical synthesis and tissue distribution studies on six fluorine-subsituted androgens, potential imaging agents for prostatic cancer. J Nucl Med 1992;33:724–34.PubMedGoogle Scholar
  187. 187.
    Bonasera TA, O’Neil JP, Xu M, et al. Preclinical evaluation of fluorine-18-labeled androgen receptor ligands in baboons. J Nucl Med 1996;37:1009–15.PubMedGoogle Scholar
  188. 188.
    Downer JB, Jones LA, Engelbach JA, et al. Comparison of animal models for the evaluation of radiolabeled androgens. Nucl Med Biol 2001;28:613–26.CrossRefPubMedGoogle Scholar
  189. 189.
    Labaree DC, Hoyte RM, Nazareth LV, et al. 7α-iodo and 7α-fluoro steroids as androgen receptor mediated imaging agent. J Med Chem 1999;3:2021–34.CrossRefGoogle Scholar
  190. 190.
    Garg PK, Labaree DC, Hoyte RM, et al. [7[α]-18F]fluoro-17[α]-methyl-5[α]-dihydrotestosterone: a ligand for androgen receptor-mediated imaging of prostate cancer. Nucl Med Biol 2001;28:85–90.CrossRefPubMedGoogle Scholar
  191. 191.
    Wang GL, Semenza GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993;268:21513–8.PubMedGoogle Scholar
  192. 192.
    Hockel M, Schlenger K, Aral B, et al. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996;56:4509–15.PubMedGoogle Scholar
  193. 193.
    Hlatky L, Tsionou C, Hanhfeldt P, et al. Mammary fibroblasts may influence breast tumor angiogenesis, via hypoxia-induced vascular endothelial growth factor upregulation and protein expression. Cancer Res 1994;54:6083–6.PubMedGoogle Scholar
  194. 194.
    Graeber TG, Osmanian C, Jacks T, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996;379:88–91.CrossRefPubMedGoogle Scholar
  195. 195.
    Rice GC, Ling V, Schimke RT. Frequencies of independent and simultaneous selection of Chinese hamster cells for methotrexate and doxorubicin (adriamycin) resistance. Proc Natl Acad Sci U S A 1987;84:9261–4.PubMedGoogle Scholar
  196. 196.
    Rice GC, Hoy C, Schimke RT. Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells. Proc Natl Acad Sci U S A 1986;83:5978–82.PubMedGoogle Scholar
  197. 197.
    Teicher BA. Physiologic mechanisms of therapeutic resistance. Hematol Oncol Clin North Am 1995;9:475–506.PubMedGoogle Scholar
  198. 198.
    Brizel DM, Sibley GS, Prosnitz LR, et al. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38:285–9.CrossRefPubMedGoogle Scholar
  199. 199.
    Gatenby RA, Kessler HB, Rosenblum JS, et al. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1988;14:831–8.PubMedGoogle Scholar
  200. 200.
    Brizel DM, Scully SP, Harrelson JM, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996;56:941–3.PubMedGoogle Scholar
  201. 201.
    Moulder JE, Rockwell S. Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data. Int J Radiat Oncol Biol Phys 1984;10:695–712.PubMedGoogle Scholar
  202. 202.
    Chapman JD, Baer K, Lee J. Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. Cancer Res 1983;43:1523–8.PubMedGoogle Scholar
  203. 203.
    Ballinger JR. Imaging hypoxia in tumors. Semin Nucl Med 2001;31:321–9.PubMedGoogle Scholar
  204. 204.
    Cater DB, Silver IA. Quantitative measurements of oxygen tension in normal tissues and in tumors of patients before and after radiotherapy. Acta Radiol 1960;53:233–56.PubMedGoogle Scholar
  205. 205.
    Bentzen L, Keiding S, Horsman MR, et al. Assessment of hypoxia in experimental mice tumours by [18F]fluoromisonidazole PET and pO2 electrode measurements. Influence of tumour volume and carbogen breathing. Acta Oncol 2002;41:304–12.CrossRefPubMedGoogle Scholar
  206. 206.
    Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1996;41:31–9.PubMedGoogle Scholar
  207. 207.
    Nordsmark M, Bentzen SM, Overgaard J. Measurement of human tumour oxygenation status by a polarographic needle electrode. An analysis of inter- and intratumour heterogeneity. Acta Oncol 1994;33:383–9.PubMedGoogle Scholar
  208. 208.
    Chapman JD, Schneider RF, Urbain JL, et al. Single photon emission computed tomography and positron-emission tomography assays for tissue oxygenation. Semin Radiat Oncol 2001;11:47–57.CrossRefPubMedGoogle Scholar
  209. 209.
    Chapman JD, Franko AJ, Sharplin J. A marker for hypoxic cells in tumours with potential clinical applicability. Br J Cancer 1981;43:546–50.PubMedGoogle Scholar
  210. 210.
    Chapman JD. Hypoxic sensitizers: implications for radiation therapy. N Engl J Med 1979;301:1429–32.PubMedGoogle Scholar
  211. 211.
    Workman P Keynote. Bioreductive mechanisms. Int J Radiat Oncol Biol Phys 1992;22:631–7.PubMedGoogle Scholar
  212. 212.
    Chapman JD, Lee J, Meeker BE. Adduct formation by 2-nitroimidazole drugs in mammalian cells: optimization of markers for tissue oxygenation. In: Adams GE, Breccia A, Fielden EM, Wardman P, editors. Selective activation of drugs by redox processes. New York: Plenum; 1990. p. 313–23.Google Scholar
  213. 213.
    Chapman JD, Baer K, Lee J. Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. Cancer Res 1983;43:1523–8.PubMedGoogle Scholar
  214. 214.
    Yang DJ, Wallace S, Cherif A, et al. Development of F-18-labeled fluoroerythronitroimidazole as a PET agent for imaging tumor hypoxia. Radiology 1995;194:795–800.PubMedGoogle Scholar
  215. 215.
    Lord EM, Harwell L, Koch CJ. Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts. Cancer Res 1993;53:5721–6.PubMedGoogle Scholar
  216. 216.
    Raleigh JA, Miller GG, Franko AJ, et al. Fluorescence immunohistochemical detection of hypoxic cells in spheroids and tumours. Br J Cancer 1987;56:395–400.PubMedGoogle Scholar
  217. 217.
    Raleigh JA, Franko AJ, Kelly DA, et al. Development of an in vivo 19F magnetic resonance method for measuring oxygen deficiency in tumors. Magn Reson Med 1991;22:451–66.PubMedGoogle Scholar
  218. 218.
    Rasey JS, Grunbaum Z, Magee S, et al. Characterization of radiolabeled fluoromisonidazole as a probe for hypoxic cells. Radiat Res 1987;111:292–304.PubMedGoogle Scholar
  219. 219.
    Seddon BM, Maxwell RJ, Honess DJ, et al. Validation of the fluorinated 2-nitroimidazole SR-4554 as a noninvasive hypoxia marker detected by magnetic resonance spectroscopy. Clin Cancer Res 2002;8:2323–35.PubMedGoogle Scholar
  220. 220.
    Hodgkiss RJ, Jones G, Long A, et al. Flow cytometric evaluation of hypoxic cells in solid experimental tumours using fluorescence immunodetection. Br J Cancer 1991;63:119–25.PubMedGoogle Scholar
  221. 221.
    Chapman JD, Engelhardt EL, Stobbe CC, et al. Measuring hypoxia and predicting tumor radioresistance with nuclear medicine assays. Radiother Oncol 1998;46:229–37.CrossRefPubMedGoogle Scholar
  222. 222.
    Koh WJ, Bergman KS, Rasey JS, et al. Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography. Int J Radiat Oncol Biol Phys 1995;33:391–8.CrossRefPubMedGoogle Scholar
  223. 223.
    Koh WJ, Rasey JS, Evans ML, et al. Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole. Int J Radiat Oncol Biol Phys 1992;22:199–212.PubMedGoogle Scholar
  224. 224.
    Rasey JS, Koh WJ, Evans ML, et al. Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int J Radiat Oncol Biol Phys 1996;36:417–28.CrossRefPubMedGoogle Scholar
  225. 225.
    Urtasun RC, McEwan AJ, Parliament MB, et al. Measurement of hypoxia in human tumors by SPECT imaging of iodoazomycin arabinoside. Br J Cancer 1996;74:209–12.Google Scholar
  226. 226.
    Parliament MB, Chapman JD, Urtasun RC, et al. Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: preliminary report of a clinical study. Br J Cancer 1992;65:90–5.PubMedGoogle Scholar
  227. 227.
    Grierson JR, Link JM, Mathis CA, et al. A radiosynthesis of fluorine-18 fluoromisonidazole. J Nucl Med 1989;30:343–50.PubMedGoogle Scholar
  228. 228.
    Piert M, Machulla H, Becker G, et al. Introducing fluorine-18 fluoromisonidazole positron emission tomography for the localisation and quantification of pig liver hypoxia. Eur J Nucl Med 1999;26:95–109.CrossRefPubMedGoogle Scholar
  229. 229.
    Lim JL, Berridge MS. An efficient radiosynthesis of [18F]fluoromisonidazole. Appl Radiat Isot 1993;44:1085–91.CrossRefPubMedGoogle Scholar
  230. 230.
    Cherif A, Yang DJ, Tansey W, et al. Rapid synthesis of 3-[18F]fluoro-1-(2′-nitro-1′-imidazolyl)-2-propanol ([18F]fluoromisonidazole). Pharm Res 1994;11:466–9.CrossRefPubMedGoogle Scholar
  231. 231.
    Rasey JS, Koh WJ, Grierson JR, et al. Radiolabelled fluoromisonidazole as an imaging agent for tumor hypoxia. Int J Radiat Oncol Biol Phys 1989;17:985–91.PubMedGoogle Scholar
  232. 232.
    Rasey JS, Nelson NJ, Chin L, et al. Characteristics of the binding of labeled fluoromisonidazole in cells in vitro. Radiat Res 1990;122:301–8.PubMedGoogle Scholar
  233. 233.
    Casciari JJ, Rasey JS. Determination of the radiobiologically hypoxic fraction in multicellular spheroids from data on the uptake of [3H]fluoromisonidazole. Radiat Res 1995;141:28–36.PubMedGoogle Scholar
  234. 234.
    Casciari JJ, Graham MM, Rasey JS. A modeling approach for quantifying tumor hypoxia with [F-18]fluoromisonidazole PET time-activity data. Med Phys 1995;22:1127–39.CrossRefPubMedGoogle Scholar
  235. 235.
    Rasey JS, Casciari JJ, Hofstrand PD, et al. Determining hypoxic fraction in a rat glioma by uptake of radiolabeled fluoromisonidazole. Radiat Res 2000;153:84–92.PubMedGoogle Scholar
  236. 236.
    Piert M, Machulla HJ, Becker G, et al. Dependency of the [18F]fluoromisonidazole uptake on oxygen delivery and tissue oxygenation in the porcine liver. Nucl Med Biol 2000;27:693–700.CrossRefPubMedGoogle Scholar
  237. 237.
    Koh WJ, Rasey JS, Evans ML, et al. Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole. Int J Radiat Oncol Biol Phys 1992;22:199–212.PubMedGoogle Scholar
  238. 238.
    Valk PE, Mathis CA, Prados MD, et al. Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med 1992;33:2133–7.PubMedGoogle Scholar
  239. 239.
    Martin GV, Caldwell JH, Graham MM, et al. Noninvasive detection of hypoxic myocardium using fluorine-18-fluoromisonidazole and positron emission tomography. J Nucl Med 1992;33:2202–8.PubMedGoogle Scholar
  240. 240.
    Yeh SH, Liu RS, Wu LC, et al. Fluorine-18 fluoromisonidazole tumour to muscle retention ratio for the detection of hypoxia in nasopharyngeal carcinoma. Eur J Nucl Med 1996;23:1378–83.PubMedGoogle Scholar
  241. 241.
    Rajendran JG, Wilson DC, Conrad EU, et al. [18F]FMISO and [18F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression. Eur J Nucl Med Mol Imaging 2003;30:695–704.Google Scholar
  242. 242.
    Koh WJ, Bergman KS, Rasey JS, et al. Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography. Int J Radiat Oncol Biol Phys 1995;33:391–8.CrossRefPubMedGoogle Scholar
  243. 243.
    Bentzen L, Keiding S, Horsman MR, et al. Feasibility of detecting hypoxia in experimental mouse tumours with 18F-fluorinated tracers and positron emission tomography—a study evaluating [18F]fluoro-2-deoxy-d-glucose. Acta Oncol 2000;39:629–37.CrossRefPubMedGoogle Scholar
  244. 244.
    Gronroos T, Eskola O, Lehtio K, et al. Pharmacokinetics of [18F]FETNIM: a potential marker for PET. J Nucl Med 2001;42:1397–404.PubMedGoogle Scholar
  245. 245.
    Lehtio K, Oikonen V, Gronroos T, et al. Imaging of blood flow and hypoxia in head and neck cancer: initial evaluation with [15O]H2O and [18F]fluoroerythronitroimidazole PET. J Nucl Med 2001;42:1643–52.PubMedGoogle Scholar
  246. 246.
    Tolvanen T, Lehtio K, Kulmala J, et al. 18F-fluoroerythronitroimidazole radiation dosimetry in cancer studies. J Nucl Med 2002;43:1674–80.PubMedGoogle Scholar
  247. 247.
    Lehtio K, Oikonen V, Nyman S, et al. Quantifying hypoxia with fluorine-18 fluoroerythronitrimidazole ([18F]FETNIM) and PET using the tumour to plasma ratio. Eur J Nucl Med Mol Imaging 2003;30:101–8.CrossRefPubMedGoogle Scholar
  248. 248.
    Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants to multiple-time uptake data. J Cereb Blood Flow Metab 1985;5:584–90.PubMedGoogle Scholar
  249. 249.
    Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol 2000;27:661–70.CrossRefPubMedGoogle Scholar
  250. 250.
    Rasey JS, Hofstrand PD, Chin LK, et al. Characterization of [18F]fluoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia. J Nucl Med 1999;40:1072–9.PubMedGoogle Scholar
  251. 251.
    Kachur AV, Dolbier WR Jr, Evans SM, et al. Synthesis of new hypoxia markers EF1 and [18F]-EF1. Appl Radiat Isot 1999;51:643–50.CrossRefPubMedGoogle Scholar
  252. 252.
    Evans SM, Joiner B, Jenkins WT, et al. Identification of hypoxia in cells and tissues of epigastric 9L rat glioma using EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide]. Br J Cancer 1995;72:875–82.PubMedGoogle Scholar
  253. 253.
    Evans SM, Jenkins WT, Joiner B, et al. 2-Nitroimidazole (EF5) binding predicts radiation resistance in individual 9L s.c. tumors. Cancer Res 1996;56:405–11.PubMedGoogle Scholar
  254. 254.
    Koch CJ, Evans SM, Lord EM. Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide]: analysis of drug adducts by fluorescent antibodies vs bound radioactivity. Br J Cancer 1995;72:869–74.PubMedGoogle Scholar
  255. 255.
    Dolbier WRJ, Li A-R, Koch CJ, et al. [18F]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a nex fluorination procedure. Appl Radiat Isot 2001;54:73–80.CrossRefPubMedGoogle Scholar
  256. 256.
    Ziemer LS, Evans SM, Kachur AV, et al. Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5. Eur J Nucl Med Mol Imaging 2003;30:259–66.PubMedGoogle Scholar
  257. 257.
    Evans SM, Kachur AV, Shiue CY, et al. Noninvasive detection of tumor hypoxia using the 2-nitroimidazole [18F]EF1. J Nucl Med 2000;41:327–36.PubMedGoogle Scholar
  258. 258.
    Yamamoto F, Aoki M, Furusawa Y, et al. Synthesis and evaluation of 4-bromo-1-(3-[18F]fluoropropyl)-2-nitroimidazole with a low energy LUMO orbital designed as brain hypoxia-targeting imaging agent. Biol Pharm Bull 2002;25:616–21.CrossRefPubMedGoogle Scholar
  259. 259.
    Blau M, Nagler W, Bender MA. Fluorine-18: a new isotope for bone scanning. J Nucl Med 1962;3:332–4.PubMedGoogle Scholar
  260. 260.
    Galasko CSB. The pathological basis for skeletal scintigraphy. J Bone Joint Surg Br 1975;57:353–9.PubMedGoogle Scholar
  261. 261.
    Messa C, Goodman WG, Hoh CK, et al. Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry. J Clin Endocrinol Metab 1993;77:949–55.CrossRefPubMedGoogle Scholar
  262. 262.
    Berger F, Lee YP, Loening AM, et al. Whole-body skeletal imaging in mice utilizing micro-PET: optimization of reproducibility and applications in animal models of bone disease. Eur J Nucl Med Mol Imaging 2002;29:1225–36.CrossRefPubMedGoogle Scholar
  263. 263.
    Petren-Mallmin M. Clinical and experimental imaging of breast cancer metastases in the spine. Acta Radiol Suppl 1994;391:1–23.PubMedGoogle Scholar
  264. 264.
    Petren-Mallmin M, Andreasson I, Ljunggren O, et al. Skeletal metastases from breast cancer: uptake of 18F-fluoride measured with positron emission tomography in correlation with CT. Skeletal Radiol 1998;27:72–6.CrossRefPubMedGoogle Scholar
  265. 265.
    Schirrmeister H, Guhlmann A, Kotzerke J. Early detection and accurate description of extent of metastatic bone disease in breast cancer with fluoride ion and positron emission tomography. J Clin Oncol 1999;17:2381–9.PubMedGoogle Scholar
  266. 266.
    Schirrmeister H, Guhlmann A, Elsner K. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J Nucl Med 1999;40:1623–9.PubMedGoogle Scholar
  267. 267.
    Schirrmeister H, Glatting G, Hetzel J, et al. Prospective evaluation of the clinical value of planar bone scans, SPECT, and 18F-labeled NaF PET in newly diagnosed lung cancer. J Nucl Med 2001;42:1800–4.PubMedGoogle Scholar
  268. 268.
    Heidelberger C. Fluorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature 1957;179:663–6.PubMedGoogle Scholar
  269. 269.
    Heidelberger C. Fluorinated pyrimidines. Prog Nucleic Acid Res Mol Biol 1965;4:1–50.PubMedGoogle Scholar
  270. 270.
    Vine EN, Young D, Vine WH, et al. An improved synthesis of 18F-5-fluorouracil. Int J Appl Radiat Isot 1979;30:401–5.CrossRefPubMedGoogle Scholar
  271. 271.
    Fowler JS, Finn RD, Lambrecht RM, et al. The synthesis of 18F-5-fluorouracil. VII. J Nucl Med 1973;14:63–4.PubMedGoogle Scholar
  272. 272.
    Wiley AL Jr, Ramirez G, Johnson RO, et al. Treatment of carcinoma of base of tongue with radiation therapy and 5-fluorouracil. Potential for optimization with 18F-FU. Acta Radiol Oncol Radiat Phys Biol 1979;18:235–43.PubMedGoogle Scholar
  273. 273.
    Shani J, Wolf W. A model for prediction of chemotherapy response to 5-fluorouracil based on the differential distribution of 5-[18F]fluorouracil in sensitive versus resistance lymphocytic leukemia in mice. Cancer Res 1977;37:2306–8.PubMedGoogle Scholar
  274. 274.
    Shani J, Wolf W, Schlesinger T, et al. Distribution of 18F-5-fluorouracil in tumor-bearing mice and rats. Int J Nucl Med Biol 1978;5:19–28.CrossRefPubMedGoogle Scholar
  275. 275.
    Lieberman LM, Wessels BW, Wiley AL Jr, et al. 18F-5-fluorouracil studies in humans and animals. Int J Radiat Oncol Biol Phys 1980;6:505–9.PubMedGoogle Scholar
  276. 276.
    Neirinckx RD, Lambrecht RM, Wolf AP. Cyclotron isotopes and radiopharmaceuticals XXV. An anhydrous 18F-fluorinating intermediate: trifluoromethyl hypoflurite. Int J Appl Radiat Isot 1978;29:323–7.CrossRefGoogle Scholar
  277. 277.
    Visser GWM, Boele S, Van Halteren BW, et al. Mechanism and stereochemistry of the fluorination of uracil and cytosine using fluorine and acetyl hypofluorite. J Org Chem 1986;51:1466–71.Google Scholar
  278. 278.
    Visser GWM, Herder RE, De Kanter FJJ, et al. Fluorination of pyrimidines. Part 2. Mechanistic aspects of the reaction of acetyl hypofluorite with uracil and cytosine derivatives. J Chem Soc Perkin Trans I 1988;1203–7.Google Scholar
  279. 279.
    Visser WMG, Gorree GCM, Braakhuis BJM, et al. An optimized synthesis of 18F-labelled-5-fluorouracil and a reevaluation of its use as a prognostic agent. Eur J Nuc Med 1989;15:225–9.Google Scholar
  280. 280.
    Brown G, Brady F, Roberts AD, et al. Improved radiosynthesis of 5-[18F]fluorouracil. J Label Compd Radiopharm 1999;42(Suppl 1):S533–5.Google Scholar
  281. 281.
    Ishiwata K, Ido T, Kawashima K, et al. Studies on 18F-labeled pyrimidines. II. Metabolic investigation of 18F-5-fluorouracil, 18F-5-fluoro-2′-deoxyuridine and 18F-5-fluorouridine in rats. Eur J Nucl Med 1984;9:185–9.PubMedGoogle Scholar
  282. 282.
    Ishiwata K, Ido T, Abe Y, et al. Studies on 18F-labeled pyrimidines. III. Biochemical investigation of 18F-labeled pyrimidines and comparison with 3H-deoxythymidine in tumor-bearing rats and mice. Eur J Nucl Med 1985;10(1–2):39–44.Google Scholar
  283. 283.
    Shani J, Young D, Schlesinger T, et al. Dosimetry and preliminary human studies of 18F-5-fluorouracil. Int J Nucl Med Biol 1982;9:25–35.CrossRefPubMedGoogle Scholar
  284. 284.
    Shani J, Manaka RC, Young D, et al. Comparative radiopharmacokinetics of 18F-5-fluorouracil administered i.v. to rats bearing a mammary tumor. Int J Nucl Med Biol 1985;12:9–12.CrossRefPubMedGoogle Scholar
  285. 285.
    Baker SD. Pharmacology of fluorinated pyrimidines: eniluracil. Invest New Drugs 2000;18:373–81.CrossRefPubMedGoogle Scholar
  286. 286.
    Bading JR, Alauddin MM, Fissekis JD, et al. Blocking catabolism with eniluracil enhances PET studies of 5-[18F]fluorouracil pharmacokinetics. J Nucl Med 2000;41:1714–24.PubMedGoogle Scholar
  287. 287.
    Visser GW, van der Wilt CL, Wedzinga R, et al. 18F-radiopharmacokinetics of [18F]-5-fluorouracil in a mouse bearing two colon tumors with a different 5-fluorouracil sensitivity: a study for a correlation with oncological results. Nucl Med Biol 1996;23:333–42.CrossRefPubMedGoogle Scholar
  288. 288.
    Young D, Vine E, Ghanbarpour A, et al. Metabolic and distribution studies with radiolabeled 5-fluorouracil. Nuklearmedizin 1982;21:1–7.PubMedGoogle Scholar
  289. 289.
    Hohenberger P, Strauss LG, Lehner B, et al. Perfusion of colorectal liver metastases and uptake of fluorouracil assessed by H2(15)O and [18F]uracil positron emission tomography (PET). Eur J Cancer 1993;29A:1682–6.CrossRefPubMedGoogle Scholar
  290. 290.
    Port RE, Strauss LG, Clorius JH. Positron emission tomography following brief infusion of 5-[18F]uracil: linear model for the kinetics of 18F radioactivity in tumors. Onkologie 1989;12(Suppl 1):51–2.Google Scholar
  291. 291.
    Dimitrakopoulou A, Strauss LG, Clorius JH, et al. Studies with positron emission tomography after systemic administration of fluorine-18-uracil in patients with liver metastases from colorectal carcinoma. J Nucl Med 1993;34:1075–81.PubMedGoogle Scholar
  292. 292.
    Dimitrakopoulou-Strauss A, Strauss LG, Schlag P, et al. Fluorine-18-fluorouracil to predict therapy response in liver metastases from colorectal carcinoma. J Nucl Med 1998;39:1197–202.PubMedGoogle Scholar
  293. 293.
    Kissel J, Brix G, Bellemann ME, et al. Pharmacokinetic analysis of 5-[18F]fluorouracil tissue concentrations measured with positron emission tomography in patients with liver metastases from colorectal adenocarcinoma. Cancer Res 1997;57:3415–23.PubMedGoogle Scholar
  294. 294.
    Moehler M, Dimitrakopoulou-Strauss A, Gutzler F, et al. 18F-labeled fluorouracil positron emission tomography and the prognoses of colorectal carcinoma patients with metastases to the liver treated with 5-fluorouracil. Cancer 1998;83:245–53.CrossRefPubMedGoogle Scholar
  295. 295.
    Saleem A, Yap J, Osman S, et al. Modulation of fluorouracil tissue pharmacokinetics by eniluracil: in vivo imaging of drug action. Lancet 2000;355:2125–31.CrossRefPubMedGoogle Scholar
  296. 296.
    Aboagye EO, Saleem A, Cunningham VJ, et al. Extraction of 5-fluorouracil by tumor and liver: a noninvasive positron emission tomography study of patients with gastrointestinal cancer. Cancer Res 2001;61:4937–41.PubMedGoogle Scholar
  297. 297.
    Haubner R, Kuhnast B, Mang C, Weber WA, Kessler H, Wester HJ, Schwaiger M. [18F]Galacto-RGD: synthesis, radiolabeling, metabolic stability, and radiation dose estimates. Bioconjug Chem 2004;15:61–9.CrossRefPubMedGoogle Scholar
  298. 298.
    Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, Senekowitsch-Schmidtke R, Kessler H, Schwaiger M. Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 2001;61:1781–5.PubMedGoogle Scholar
  299. 299.
    Chen X, Park R, Tohme M, Shahinian AH, Bading JR, Conti PS. MicroPET and autoradiographic imaging of breast cancer alpha v-integrin expression using 18F- and 64Cu-labeled RGD peptide. Bioconjug Chem 2004;15:41–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Olivier Couturier
    • 1
  • André Luxen
    • 2
  • Jean-François Chatal
    • 1
  • Jean-Philippe Vuillez
    • 3
  • Pierre Rigo
    • 4
  • Roland Hustinx
    • 5
    Email author
  1. 1.Division of Nuclear MedicineHôtel DieuNantesFrance
  2. 2.Centre de Recherche du CyclotronUniversity of LiègeLiègeBelgium
  3. 3.Division of Nuclear MedicineGrenobleFrance
  4. 4.Division of Nuclear MedicineHôpital Princesse GraceMonte CarloMonaco
  5. 5.Division of Nuclear MedicineCHULiègeBelgium

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