microPET of tumor integrin alphavbeta3 expression using 18F-labeled PEGylated tetrameric RGD peptide (18F-FPRGD4).
In vivo imaging of alpha(v)beta(3) expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin alpha(v)beta(3)-binding affinity due to the polyvalency effect. Here we report an example of (18)F-labeled tetrameric RGD peptide for PET of alpha(v)beta(3) expression in both xenograft and spontaneous tumor models.


METHODS
The tetrameric RGD peptide E{E[c(RGDyK)](2)}(2) was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate alpha-amino group. NH(2)-mini-PEG-E{E[c(RGDyK)](2)}(2) (PRGD4) was labeled with (18)F via the N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer (18)F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies.


RESULTS
The decay-corrected radiochemical yield for (18)F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from (18)F-F(-). The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. (18)F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of (18)F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK).


CONCLUSIONS
The tetrameric RGD peptide tracer (18)F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin alpha(v)beta(3) expression in cancer and other angiogenesis related diseases.
Wu
Zhanhong
Z
The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305, USA.
Li
Zi-Bo
ZB
Chen
Kai
K
Cai
Weibo
W
He
Lina
L
Chin
Frederick T
FT
Li
Fang
F
Chen
Xiaoyuan
X
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods; D014183:Transplantation, Heterologous
D005462:Fluorine Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid
Cancer Res. 2001 Mar 1;61(5):1781-5
11280722
Neurosurgery. 2001 Aug;49(2):380-9; discussion 390
11504114
Clin Pharmacokinet. 2001;40(7):539-51
11510630
Lab Invest. 2001 Dec;81(12):1615-26
11742032
Cancer Biother Radiopharm. 2002 Dec;17(6):641-6
12537667
Antimicrob Agents Chemother. 2003 Feb;47(2):554-8
12543658
Nephron Exp Nephrol. 2003;93(2):e72
12629275
Chemistry. 2003 Jun 16;9(12):2717-25
12772286
Int J Rad Appl Instrum A. 1992 Oct;43(10):1265-74
1330979
Cancer Biother Radiopharm. 2003 Aug;18(4):627-41
14503959
Bioconjug Chem. 2004 Jan-Feb;15(1):41-9
14733582
Nucl Med Biol. 2004 Feb;31(2):179-89
15013483
Bioconjug Chem. 2004 Mar-Apr;15(2):235-41
15025518
J Nucl Med. 2004 May;45(5):892-902
15136641
Mol Imaging. 2004 Apr;3(2):96-104
15296674
Mol Imaging Biol. 2004 Sep-Oct;6(5):350-9
15380745
J Nucl Med. 2004 Oct;45(10):1776-83
15471848
Hematol Oncol Clin North Am. 2004 Oct;18(5):991-1006, vii
15474331
J Nucl Med. 2005 Jan;46(1):184-9
15632051
J Cardiovasc Pharmacol. 2005 Feb;45(2):109-13
15654258
J Nucl Med. 2005 Aug;46(8):1333-41
16085591
J Nucl Med. 2005 Oct;46(10):1707-18
16204722
Bioconjug Chem. 2005 Nov-Dec;16(6):1433-41
16287239
J Nucl Med. 2006 Jan;47(1):113-21
16391195
Mini Rev Med Chem. 2006 Feb;6(2):227-34
16472190
J Nucl Med. 2006 May;47(5):763-9
16644745
Clin Cancer Res. 2006 Jul 1;12(13):3942-9
16818691
J Nucl Med. 2006 Jul;47(7):1172-80
16818952
Bioconjug Chem. 2006 Sep-Oct;17(5):1294-313
16984141
Mol Pharm. 2006 Sep-Oct;3(5):472-87
17009846
Eur J Nucl Med Mol Imaging. 2007 Nov;34(11):1823-1831
17492285
Biotechniques. 2005 Dec;39(6 Suppl):S14-25
20158499
Cancer Res. 1990 Oct 15;50(20):6757-64
2208139
J Cell Physiol. 1989 May;139(2):275-86
2469686
Cell. 1988 Jul 1;54(1):105-15
2898299
Angew Chem Int Ed Engl. 1998 Nov 2;37(20):2754-2794
29711117
J Clin Invest. 1995 Oct;96(4):1815-22
7560073
Eur J Nucl Med. 1998 Feb;25(2):201-12
9473271