title: A new PET tracer specific for vascular endothelial growth factor receptor 2.
abstract: OBJECTIVE
  Noninvasive positron emission tomography (PET) imaging of vascular endothelial growth factor receptor 2 (VEGFR-2) expression could be a valuable tool for evaluation of patients with a variety of malignancies, and particularly for monitoring those undergoing antiangiogenic therapies that block VEGF/VEGFR-2 function. The aim of this study was to develop a VEGFR-2-specific PET tracer.
  
  
  METHODS
  The D63AE64AE67A mutant of VEGF(121) (VEGF(DEE)) was generated by recombinant DNA technology. VEGF(121) and VEGF(DEE) were purified and conjugated with DOTA for (64)Cu labeling. The DOTA conjugates were tested in vitro for VEGFR-2 specificity and functional activity. In vivo tumor targeting efficacy and pharmacokinetics of (64)Cu-labeled VEGF(121) and VEGF(DEE) were compared using an orthotopic 4T1 murine breast tumor model. Blocking experiments, biodistribution studies, and immunofluorescence staining were carried out to confirm the noninvasive imaging results.
  
  
  RESULTS
  Cell binding assay demonstrated that VEGF(DEE) had about 20-fold lower VEGFR-1 binding affinity and only slightly lower VEGFR-2 binding affinity as compared with VEGF(121). MicroPET imaging studies revealed that both (64)Cu-DOTA-VEGF(121) and (64)Cu-DOTA-VEGF(DEE) had rapid and prominent activity accumulation in VEGFR-2-expressing 4T1 tumors. The renal uptake of (64)Cu-DOTA-VEGF(DEE) was significantly lower than that of (64)Cu-DOTA-VEGF(121) as rodent kidneys expressed high levels of VEGFR-1 based on immunofluorescence staining. Blocking experiments and biodistribution studies confirmed the VEGFR specificity of (64)Cu-DOTA-VEGF(DEE).
  
  
  CONCLUSIONS
  We have developed a VEGFR-2-specific PET tracer, (64)Cu-DOTA-VEGF(DEE). It has comparable tumor targeting efficacy to (64)Cu-DOTA-VEGF(121) but much reduced renal toxicity. This tracer may be translated into the clinic for imaging tumor angiogenesis and monitoring antiangiogenic treatment efficacy.
authors: The Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305-5484, USA.
authors: Hui
authors: H
authors: Wang
authors: Weibo
authors: W
authors: Cai
authors: Kai
authors: K
authors: Chen
authors: Zi-Bo
authors: ZB
authors: Li
authors: Amir
authors: A
authors: Kashefi
authors: Lina
authors: L
authors: He
authors: Xiaoyuan
authors: X
authors: Chen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D045744:Cell Line, Tumor; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000493:pharmacokinetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: C529227:64Cu-DOTA-VEGF(DEE); D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
references: Q J Nucl Med Mol Imaging. 2004 Sep;48(3):198-206
references: 15499293
references: J Nucl Med. 2005 Nov;46(11):1881-8
references: 16269603
references: Cancer Res. 2000 Feb 15;60(4):970-5
references: 10706112
references: Nat Med. 1995 Jan;1(1):27-31
references: 7584949
references: Endocr Rev. 2004 Aug;25(4):581-611
references: 15294883
references: Exp Dermatol. 2004 Nov;13(11):671-81
references: 15500639
references: Clin Cancer Res. 2003 Apr;9(4):1546-56
references: 12684431
references: Cancer Res. 2006 Oct 1;66(19):9673-81
references: 17018625
references: J Clin Oncol. 2005 Feb 10;23(5):1011-27
references: 15585754
references: Ann Oncol. 2003 Aug;14(8):1274-7
references: 12881392
references: Protein Eng Des Sel. 2005 Sep;18(9):417-24
references: 16087652
references: J Am Soc Nephrol. 1998 Jun;9(6):1032-44
references: 9621286
references: J Nucl Med. 2006 Jul;47(7):1172-80
references: 16818952
references: Front Biosci. 2007 May 01;12:4267-79
references: 17485373
references: Nucl Med Biol. 2005 Jul;32(5):431-6
references: 15982572
references: EXS. 2005;(94):209-31
references: 15617481
references: Clin Cancer Res. 2004 Dec 15;10 (24):8674-82
references: 15623652
references: Cancer Res. 2000 Apr 15;60(8):2178-89
references: 10786682
references: J Nucl Med. 2007 Feb;48(2):304-10
references: 17268029
references: Curr Med Chem. 2004 Mar;11(6):731-45
references: 15032727
references: J Nucl Med. 2005 Oct;46(10 ):1745-52
references: 16204726
references: Cancer Res. 1999 Oct 15;59(20):5209-18
references: 10537299
references: Eur J Nucl Med Mol Imaging. 2007 Nov;34(11):1832-42
references: 17541586
references: J Nucl Med. 2007 Mar;48(3):445-54
references: 17332623
references: J Biol Chem. 1996 Mar 8;271(10):5638-46
references: 8621427
references: Mol Cancer Ther. 2006 Nov;5(11):2624-33
references: 17121909
references: Oncogene. 1990 Apr;5(4):519-24
references: 2158038
references: Circulation. 2003 Jul 8;108(1):97-103
references: 12821549
references: Nat Med. 2007 Apr;13(4):504-9
references: 17351626
references: Eur J Nucl Med Mol Imaging. 2006 Jul;33(7):841-8
references: 16699765
references: J Natl Cancer Inst. 2002 Oct 2;94(19):1484-93
references: 12359857
references: J Nucl Med. 2006 Dec;47(12 ):2048-56
references: 17138749
references: Neoplasia. 2005 Mar;7(3):271-9
references: 15799827
references: Nat Nanotechnol. 2007 Jan;2(1):47-52
references: 18654207
references: Oncogene. 2005 Jul 7;24(29):4701-9
references: 15897913
references: J Nucl Med. 2004 Aug;45(8):1373-80
references: 15299064
references: Nucl Med Biol. 2006 Nov;33(8):963-9
references: 17127168
references: Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9026-30
references: 1717995
references: J Med Chem. 2004 Mar 11;47(6):1465-74
references: 14998334
references: Nat Rev Cancer. 2002 Oct;2(10):795-803
references: 12360282