N3-substituted thymidine bioconjugates for cancer therapy and imaging

Future Medicinal Chemistry

Volumn 5, Issue 6, 2013, Pages 677-692

  Khalil, Ahmed ^a,b   Ishita, Keisuke ^a   Ali, Tehane ^a   Tjarks, Werner ^a  

^a OHIO STATE UNIVERSITY   (United States)

^b Zagazig University   (Egypt)

Author keywords

[No Author keywords available]

Indexed keywords

3 CARBORANYLTHYMIDINE DERIVATIVE; 4 BORONOPHENYLALANINE; 5 (1,2 CARBORANYL) 2' DEOXYURIDINE; BOROCAPTATE; BORON DERIVATIVE; CARBORANE DERIVATIVE; PACLITAXEL; PYRIMIDINE NUCLEOSIDE DERIVATIVE; THYMIDINE DERIVATIVE; THYMIDINE KINASE 1; UNCLASSIFIED DRUG; VINBLASTINE;

BRAIN TUMOR; CONJUGATE; CYTOPATHOGENIC EFFECT; DIAGNOSTIC IMAGING; DRUG ACCUMULATION; DRUG CONJUGATION; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG DISTRIBUTION; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; DRUG TARGETING; ENZYME STRUCTURE; HUMAN; MOLECULAR DOCKING; NEUTRON CAPTURE THERAPY; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; BORANES; BORON NEUTRON CAPTURE THERAPY; HUMANS; MOLECULAR DOCKING SIMULATION; NEOPLASMS; NITROGEN; PRODRUGS; THYMIDINE; THYMIDINE KINASE;

EID: 84876842084     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.13.31     Document Type: Review

References (98)

1. Barth RF, Coderre JA, Vicente MG, Blue TE. Boron neutron capture therapy of cancer: Current status and future prospects. Clin. Cancer Res. 11, 3987-4002 (2005
2. Soloway AH, Tjarks W, Barnum BA et al. The chemistry of neutron capture therapy. Chem. Rev. 98, 1515-1562 (1998
3. Das BC, Das S, Li G, Bao W, Kabalka GW. Synthesis of a water soluble carborane containing amino acid as a potential therapeutic agent. Synlett 9, 1419-1420 (2001
4. Cai J, Soloway AH, Barth RF et al. Boron containing polyamines as DNA targeting agents for neutron capture therapy of brain tumors: Synthesis and biological evaluation. J. Med. Chem. 40, 3887-3896 (1997
5. Zhuo J-C, Cai J, Soloway AH et al. Synthesis and biological evaluation of boron containing polyamines as potential agents for neutron capture therapy of brain tumors. J. Med. Chem. 42, 1282-1292 (1999
6. Tietze LF, Griesbach U, Bothe U, Nakamura H, Yamamoto Y. Novel carboranes with a DNA binding unit for the treatment of cancer by boron neutron capture therapy. Chembiochem 3, 219-225 (2002
7. Crossley EL, Ziolkowski EJ, Coderre JA, Rendina LM. Boronated DNA-binding compounds as potential agents for boron neutron capture therapy. Mini Rev. Med. Chem. 7, 303-313 (2007
8. Isaac MF, Kahl SB. Synthesis of ether- And carbon-linked polycarboranyl porphyrin dimers for cancer therapies. J. Organomet. Chem. 680, 232-243 (2003
9. Jori G, Soncin M, Friso E et al. A novel boronated-porphyrin as a radio-sensitizing agent for boron neutron capture therapy of tumors: In vitro and in vivo studies. Appl. Radiat. Isot. 67, S321-S324 (2009
10. Renner MW, Miura M, Easson MW, Vicente MGH. Recent progress in the syntheses and biological evaluation of boronated porphyrins for boron neutron-capture therapy. Anti- Cancer Agents Med. Chem. 6, 145-157 (2006
11. Tietze LF, Griesbach U, Schuberth I, Bothe U, Marra A, Dondoni A. Novel carboranyl C-glycosides for the treatment of cancer by boron neutron capture therapy. Chemistry 9, 1296-1302 (2003
12. Bregadze V, Semioshkin A, Sivaev I. Synthesis of conjugates of polyhedral boron compounds with tumor-seeking molecules for neutron capture therapy. Appl. Radiat. Isot. 69, 1774-1777 (2011
13. Bregadze VI, Sivaev IB. Polyhedral boron compounds for BNCT. In: Boron Science. Hosmane NS (Ed.). CRC Press, FL, USA, 181-207 (2012
14. Orlova AV, Kononov LO. Synthesis of conjugates of polyhedral boron compounds with carbohydrates. Russ. Chem. Rev. 78, 629-642 (2009
15. Olsson P, Gedda L, Goike H et al. Uptake of a boronated epidermal growth factor-dextran conjugate in CHO xenografts with and without human EGF-receptor expression. Anticancer Drug Des. 13, 279-289 (1998
16. Yang W, Barth RF, Wu G, Tjarks W, Binns P, Riley K. Boron neutron capture therapy of EGFR or EGFRvIII positive gliomas using either boronated monoclonal antibodies or epidermal growth factor as molecular targeting agents. Appl. Radiat. Isot. 67, S328-S331 (2009
17. Yang W, Wu G, Barth RF et al. Molecular targeting and treatment of composite EGFR and EGFRvIII-Positive gliomas using boronated monoclonal antibodies. Clin. Cancer Res. 14, 883-891 (2008
18. Carlsson J, Kullberg EB, Capala J, Sjoberg S, Edwards K, Gedda L. Ligand liposomes and boron neutron capture therapy. J. Neurooncol. 62, 47-59 (2003
19. Justus E, Awad D, Hohnholt M et al. Synthesis, liposomal preparation, and in vitro toxicity of two novel dodecaborate cluster lipids for boron neutron capture therapy. Bioconjug. Chem. 18, 1287-1293 (2007
20. Altieri S, Balzi M, Bortolussi S et al. Carborane derivatives loaded into liposomes as efficient delivery systems for boron neutron capture therapy. J. Med. Chem. 52, 7829-7835 (2009
21. Byun Y, Narayanasamy S, Johnsamuel J et al. 3-Carboranyl thymidine analogues (3CTAs) and other boronated nucleosides for boron neutron capture therapy. Anticancer Agents Med. Chem. 6, 127-144 (2006
22. Nerini-Molteni S, Seregni E, Crippa F, Maffioli L, Botti C, Bombardieri E. Uptake of tritiated thymidine, deoxyglucose and methionine in three lung cancer cell lines: Deoxyglucose uptake mirrors tritiated thymidine uptake. Tumour Biol. 22, 92-96 (2001
23. Zhang CC, Yan Z, Li W et al. [18F]FLT-PET imaging does not always "light up" proliferating tumor cells. Clin. Cancer Res. 18, 1303-1312 (2012
24. Tjarks W, Tiwari R, Byun Y, Narayanasamy S, Barth RF. Carboranyl thymidine analogues for neutron capture therapy. Chem. Commun. 47, 4978-4991 (2007
25. Aspland SE, Ballatore C, Castillo R et al. Kinase-mediated trapping of bi-functional conjugates of paclitaxel or vinblastine with thymidine in cancer cells. Bioorg. Med. Chem. Lett. 16, 5194-5198 (2006
26. Ghosh P, Pal A, Shavrin A, Bornmann W, Gelovani JG, Alauddi MM. Synthesis of N3- substituted thymidine analogues for measurement of cellular kinase activity. Med. Chem. 4, 503-512 (2008
27. Toyohara J, Hayashi A, Gogami A et al. Alkyl-fluorinated thymidine derivatives for imaging cell proliferation I. The in vitro evaluation of some alkyl-fluorinated thymidine derivatives. Nucl. Med. Biol. 33, 751-764 (2006
28. Balzarini J, Celen S, Karlsson A, De Groot T, Verbruggen A, Bormans G. The effect of a methyl or 2-fluoroethyl substituent at the N-3 position of thymidine, 3́-fluoro-3́- deoxythymidine and 1-beta-D- Trabinosylthymine on their antiviral and cytostatic activity in cell culture. Antivir. Chem. Chemother. 17, 17-23 (2006
29. Smith G, Sala R, Carroll L et al. Synthesis and evaluation of nucleoside radiotracers for imaging proliferation. Nucl. Med. Biol. 39, 652-665 (2012
30. Desbouis D, Struthers H, Spiwok V, Kuster T, Schibli R. Synthesis, in vitro, and in silico evaluation of organometallic technetium and rhenium thymidine complexes with retained substrate activity toward human thymidine kinase type 1. J. Med. Chem. 51, 6689-6698 (2008
31. Hosmane NS. Boron Science: New Technologies and Applications. CRC Press, FL, USA, (2012
32. Byun Y, Yan J, Al-Madhoun AS et al. Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy. J. Med. Chem. 48, 1188-1198 (2005
33. Issa F, Kassiou M, Rendina LM. Boron in drug discovery: Carboranes as unique pharmacophores in biologically active compounds. Chem. Rev. 111, 5701-5722 (2011
34. Scholz M, Hey-Hawkins E. Carbaboranes as pharmacophores: Properties, synthesis, and application strategies. Chem. Rev. 111, 7035-7062 (2011
35. Agarwal HK, Hasabelnaby S, Tiwari R, Tjarks W. Boron cluster (Radio) halogenation in biomedical research. In: Boron Science. Hosmane NS (Ed.). CRC Press, FL, USA, 107-144 (2012
36. Welin M, Kosinska U, Mikkelsen NE et al. Structures of thymidine kinase 1 of human and mycoplasmic origin. Proc. Natl Acad. Sci. USA 101, 17970-17975 (2004
37. Kosinska U, Carnrot C, Eriksson S, Wang L, Eklund H. Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme. FEBS J. 272, 6365-6372 (2005
38. Segura-Pena D, Lutz S, Monnerjahn C, Konrad M, Lavie A. Binding of ATP to TK1- like enzymes is associated with a conformational change in the quaternary structure. J. Mol. Biol. 369, 129-141 (2007
39. Birringer MS, Claus MT, Folkers G, Kloer DP, Schulz GE, Scapozza L. Structure of a type II thymidine kinase with bound dTTP. FEBS Lett. 579, 1376-1382 (2005
40. Segura-Pena D, Lichter J, Trani M, Konrad M, Lavie A, Lutz S. Quaternary structure change as a mechanism for the regulation of thymidine kinase 1-like enzymes. Structure 15, 1555-1566 (2007
41. Kosinska U, Carnrot C, Sandrini MP et al. Structural studies of thymidine kinases from Bacillus anthracis and Bacillus cereus provide insights into quaternary structure and conformational changes upon substrate binding. FEBS J. 274, 727-737 (2007
42. El Omari K, Solaroli N, Karlsson A, Balzarini J, Stammers DK. Structure of vaccinia virus thymidine kinase in complex with dTTP: Insights for drug design. BMC Struct. Biol. 6, 22 (2006
43. Al-Madhoun AS, Tjarks W, Eriksson S. The role of thymidine kinases in the activation of pyrimidine nucleoside analogues. Mini Rev. Med. Chem. 4, 341-350 (2004
44. Arner ES, Eriksson S. Mammalian deoxyribonucleoside kinases. Pharmacol. Ther. 67, 155-186 (1995
45. Eriksson S, Munch-Petersen B, Johansson K, Eklund H. Structure and function of cellular deoxyribonucleoside kinases. Cell. Mol. Life Sci. 59, 1327-1346 (2002
46. Priego EM, Karlsson A, Gago F, Camarasa MJ, Balzarini J, Perez-Perez MJ. Recent advances in thymidine kinase 2 (TK2) inhibitors and new perspectives for potential applications. Curr. Pharm. Des. 18, 2981-2994 (2012
47. Kauffman MG, Kelly TJ. Cell cycle regulation of thymidine kinase: Residues near the carboxyl terminus are essential for the specific degradation of the enzyme at mitosis. Mol. Cell. Biol. 11, 2538-2546 (1991
48. Eriksson S, Kierdaszuk B, Munch-Petersen B, Oberg B, Johansson NG. Comparison of the substrate specificities of human thymidine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogs. Biochem. Biophys. Res. Commun. 176, 586-592 (1991
49. Hanan S, Jagarlamudi KK, Liya W, Ellen H, Staffan E. Quaternary structures of recombinant, cellular, and serum forms of thymidine kinase 1 from dogs and humans. BMC Biochem. 13, 12 (2012
50. Johansson NG, Eriksson S. Structure-Tctivity relationships for phosphorylation of nucleoside analogs to monophosphates by nucleoside kinases. Acta Biochim. Pol. 43, 143-160 (1996
51. Bodei L, Kassis AI, Adelstein SJ, Mariani G. Radionuclide therapy with iodine-125 and other auger-electron-emitting radionuclides: Experimental models and clinical applications. Cancer Biother. Radiopharm. 18, 861-877 (2003
52. Russo A, Gianni L, Kinsella TJ et al. Pharmacological evaluation of intravenous delivery of 5-bromodeoxyuridine to patients with brain tumors. Cancer Res. 44, 1702-1705 (1984
53. Schinazi RF, Prusoff WH. Synthesis of 5-(dihydroxyboryl)-2́- deoxyuridine and related boron containing pyrimidines. J. Org. Chem. 50, 841-847 (1985
54. Goudgaon NM, Fulcrand E-KG, Schinazi RF. Boron containing pyrimidines, nucleosides, and oligonucleotides for neutron capture therapy. Nucleosides Nucleotides 13, 849-880 (1994
55. Yamamoto Y, Seko T, Nakamura H et al. Synthesis of carboranes containing nucleoside bases. Unexpectedly high cytostatic and cytocidal toxicity towards cancer cells. Chem. Comm. 2, 157-158 (1992
56. Lunato AJ, Wang J, Woollard JE et al. Synthesis of 5- (carboranylalkylmercapto)-2́- deoxyuridines and 3-(carboranylalkyl) thymidines and their evaluation as substrates for human thymidine kinases 1 and 2. J. Med. Chem. 42, 3378-3389 (1999
57. Lesnikowski ZJ, Shi J, Schinazi RF. Nucleic acids and nucleosides containing carboranes. J. Organomet. Chem. 581, 156-169 (1999
58. Burnham BS, Chen SY, Sood A, Spielvogel BF, Miller MC 3rd, Hall IH. The cytotoxicity of 3́-Tminocyanoborane-2́, 3́-dideoxypyrimidines in murine and human tissue cultured cell lines. Anticancer Res. 15, 951-958 (1995
59. Al-Madhoun AS, Johnsamuel J, Barth RF, Tjarks W, Eriksson S. Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy. Cancer Res. 64, 6280-6286 (2004
60. Barth RF, Yang W, Al-Madhoun AS et al. Boron containing nucleosides as potential delivery agents for neutron capture therapy of brain tumors. Cancer Res. 64, 6287-6295 (2004
61. Byun Y, Thirumamagal BT, Yang W, Eriksson S, Barth RF, Tjarks W. Preparation and biological evaluation of 10B-enriched 3-[5-{2-(2,3- dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5- 2OH), a new boron delivery agent for boron neutron capture therapy of brain tumors. J. Med. Chem. 49, 5513-5523 (2006
62. Barth RF, Yang W, Wu G et al. Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors. Proc. Natl Acad. Sci. USA 105, 17493-17497 (2008
63. Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues: Mechanisms of drug resistance and reversal strategies. Leukemia 15, 875-890 (2001
64. Lowe CR, Incropera FP, DeWitt DP, Dean PDG. Affinity Chromatography. Lowe CR, Dean PDG (Eds). Wiley-Interscience, NY, USA (1974
65. Lowe CR, Harvey MJ, Craven DB, Dean PD. Some parameters relevant to affinity chromatography on immobilized nucleotides. Biochem. J. 133, 499-506 (1973
66. Grobner P, Loidl P. Thymidine kinase. A novel affinity chromatography of the enzyme and its regulation by phosphorylation in Physarum polycephalum. J. Biol. Chem. 259, 8012-8014 (1984
67. Agarwal HK, McElroy CA, Sjuvarsson E, Eriksson S, Darby MV, Tjarks W. Synthesis of N3-substituted carboranyl thymidine bioconjugates and their evaluation as substrates of recombinant human thymidine kinase 1. Eur. J. Med. Chem. 60, 456-468, (2013
68. Tiwari R, Toppino A, Agarwal HK et al. Synthesis, biological evaluation, and radioiodination of halogenated closo-carboranylthymidine analogues. Inorg. Chem. 51, 629-639 (2011
69. Hasabelnaby S, Goudah A, Agarwal HK, Abd Alla MS, Tjarks W. Synthesis, chemical and enzymatic hydrolysis, and aqueous solubility of amino acid ester prodrugs of 3-carboranyl thymidine analogs for boron neutron capture therapy of brain tumors. Eur. J. Med. Chem. 55, 325-334 (2012
70. Davson H, Segal Mb. Physiology of the CSF and blood-brain barriers. CRC Press, FL, USA, (1996
71. Abbott NJ. Evidence for bulk flow of brain interstitial fluid: Significance for physiology and pathology. Neurochem. Int. 45, 545-552 (2004
72. Song X, Lorenzi PL, Landowski CP, Vig BS, Hilfinger JM, Amidon GL. Amino acid ester prodrugs of the anticancer agent gemcitabine: Synthesis, bioconversion, metabolic bioevasion, and hPEPT1-mediated transport. Mol. Pharm. 2, 157-167 (2005
73. Tsume Y, Vig BS, Sun J et al. Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters. Molecules 13, 1441-1454 (2008
74. Vig BS, Lorenzi PJ, Mittal S et al. Amino acid ester prodrugs of floxuridine: Synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis. Pharm. Res. 20, 1381-1388 (2003
75. Sun Y, Sun J, Shi S et al. Synthesis, transport and pharmacokinetics of 5́-Tmino acid ester prodrugs of 1-beta-D-Trabinofuranosylcytosine. Mol. Pharm. 6, 315-325 (2009
76. Johnsamuel J, Lakhi N, Al-Madhoun AS et al. Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties. Bioorg. Med. Chem. 12, 4769-4781 (2004
77. Thirumamagal BT, Johnsamuel J, Cosquer GY et al. Boronated thymidine analogues for boron neutron capture therapy. Nucleosides Nucleotides Nucleic Acids 25, 861-866 (2006
78. Narayanasamy S, Thirumamagal BT, Johnsamuel J et al. Hydrophilically enhanced 3-carboranyl thymidine analogues (3CTAs) for boron neutron capture therapy (BNCT) of cancer. Bioorg. Med. Chem. 14, 6886-6899 (2006
79. Semioshkin A, Laskova J, Wojtczak B et al. Synthesis of closo-dodecaborate based nucleoside conjugates. J. Organomet. Chem. 694, 1375-1379 (2009
80. Wojtczak BA, Andrysiak A, Gruener B, Lesnikowski ZJ. 'Chemical ligation': A versatile method for nucleoside modification with boron clusters. Chem.Eur. J. 14, 10675-10682 (2008
81. Padwa A. 1,3-Dipolar Cycloaddition Chemistry, Volume 1. John Wiley and Sons, NY, USA (1984
82. Kimura T, Watanabe K, Tateoka Y, Kondo S, Ho IK, Yamamoto I. Preparation and pharmacological evaluation of N3-substituted thymidine derivatives as central depressants. Chem. Pharm. Bull. 41, 1180-1182 (1993
83. Shimizu T, Kimura T, Funahashi T, Watanabe K, Ho IK, Yamamoto I. Synthesis of N3-substituted uridine and related pyrimidine nucleosides and their antinociceptive effects in mice. Chem. Pharm. Bull. 53, 313-318 (2005
84. Kitade Y, Suzuki A, Hirota K et al. Synthesis and anti-human immunodeficiency virus type 1 (HIV-1) activity of 3-substituted derivatives of 3́-Tzido-3́-deoxythymidine (AZT), and inhibition of HIV-1 reverse transcriptase by their 5́-triphosphates. Chem. Pharm. Bull. 40, 920-924 (1992
85. Adams DR, Perez C, Maillard M et al. Preparation and anti-HIV activity of N-3-substituted thymidine nucleoside analogs. J. Med. Chem. 40, 1550-1558 (1997
86. Alauddin MM, Ghosh P, Gelovani JG. Synthesis of [18F]-labeled N-3(substituted) thymidine analogs: N-3([18F]fluorobutyl) thymidine ([18F]-FBT) and N-3([18F] fluoropentyl) thymidine ([18F]-FPT) for PET. J. Labelled Compd. Radiopharm. 49, 1079-1088 (2006
87. Toyohara J, Hayashi A, Gogami A, Fujibayashi Y. Alkyl-fluorinated thymidine derivatives for imaging cell proliferation II. Synthesis and evaluation of N3-(2-[18F] fluoroethyl)-thymidine. Nucl. Med. Biol. 33, 765-772 (2006
88. Mukhopadhyay U, Soghomonyan S, Yeh HH et al. N(3)-Substituted thymidine analogues V: Synthesis and preliminary PET imaging of N(3)-[18F]fluoroethyl thymidine and N(3)-[18F]fluoropropyl thymidine. Nucl. Med. Biol. 35, 697-705 (2008
89. Ghosh P, Gelovani JG, Alauddin MM. N3-Substituted thymidine analogues. Part III: Radiosynthesis of N3-[(4-[18F] fluoromethyl-phenyl)butyl]thymidine ([18F]-FMPBT) and N3-[(4-[18F] fluoromethyl-phenyl)pentyl] thymidine ([18F]-FMPPT) for PET. J. Labelled Compd. Radiopharm. 50, 1185-1191 (2007
90. Ghosh P, Gelovani JG, Alauddin MM. N3-substituted thymidine analogues: Radiosyntheses of N3-[4-(4-(2-[18F] fluoroethyl)phenyl)butyl]thymidine and N3-[5-(4-(2-[18F]fluoroethyl)phenyl)pentyl] thymidine for PET. Curr. Radiopharm. 2, 2-8 (2009
91. Schmid M, Neumaier B, Vogg AT et al. Synthesis and evaluation of a radiometal-labeled macrocyclic chelator-derivatised thymidine analog. Nucl. Med. Biol. 33, 359-366 (2006
92. Mindt T, Struthers H, Garcia-Garayoa E, Desbouis D, Schibli R. Strategies for the development of novel tumor targeting technetium and rhenium radiopharmaceuticals. Chimia 61, 725-731 (2007
93. Bartholoma MD, Vortherms AR, Hillier S et al. Synthesis, cytotoxicity, and insight into the mode of action of Re(CO)3 thymidine complexes. ChemMedChem 5, 1513-1529 (2010
94. Bartholomae MD, Vortherms AR, Hillier S et al. Synthesis, cytotoxicity and cellular uptake studies of N3 functionalized Re(CO)3 thymidine complexes. Dalton Trans. 40, 6216-6225 (2011
95. Struthers H, Hagenbach A, Abram U, Schibli R. Organometallic [Re(CO)3]+ and [Re(CO)2(NO)]2+ labeled substrates for human thymidine kinase 1. Inorg. Chem. 48, 5154-5163 (2009
96. Struthers H, Spingler B, Mindt TL, Schibli R. "Click-to- chelate": Design and incorporation of triazole-containing metal-chelating systems into biomolecules of diagnostic and therapeutic interest. Chem. Eur. J. 14, 6173-6183 (2008
97. Struthers H, Viertl D, Kosinski M, Spingler B, Buchegger F, Schibli R. Charge dependent substrate activity of C3́ and N3 functionalized, organometallic technetium and rhenium-labeled thymidine derivatives toward human thymidine kinase 1. Bioconjug. Chem. 21, 622-634 (2010
98. Celen S, De Groot T, Balzarini J et al. Synthesis and evaluation of a 99mTc-MAMA-propyl-thymidine complex as a potential probe for in vivo visualization of tumor cell proliferation with SPECT. Nucl. Med. Biol. 34, 283-291 (2007