Abstract
Purpose
Angiogenesis plays a major role in tissue remodeling and repair after myocardial infarction (MI), and imaging it could provide information on the healing process. During angiogenesis, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and Tie receptors are upregulated, and this study aimed to develop a C-11 positron emission tomography (PET) agent for imaging angiogenesis by targeting these receptors.
Procedures
A VEGFR-2/Tie-2/PDGFRα inhibitor (N-(6-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-ureido]-phenoxy}-1H-benzoimidazol-2-yl)-2-(4-methyl-piperazin-1-yl)-acetamide (ATV-1)) was synthesized and labeled with C-11. MicroPET imaging of a rat MI model was compared to proteins expression by immunohistochemistry.
Results
[11C]ATV-1 specifically accumulated in the infracted region of the left ventricular (LV) lateral wall more than in the interventricular septal wall, but not in sham-operated or healthy animals. Moreover, [11C]ATV-1 uptake in the LV significantly correlated with Tie-2, VEGFR-2, and PDGFRα expression.
Conclusion
Imaging angiogenesis in MI rats using [11C]ATV-1 and PET has been demonstrated. These results merit further research and development of more hydrophilic modified [11C]ATV-1 as a PET tracer.
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References
Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507–521
Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674
Loughna S, Sato TN (2001) Angiopoietin and Tie signaling pathways in vascular development. Matrix Biol 20:319–325
Peters KG, Kontos CD, Lin PC et al (2004) Functional significance of Tie2 signaling in the adult vasculature. Recent Prog Horm Res 59:51–71
Suri C, Jones PF, Patan S et al (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180
Backer MV, Backer JM (2012) Imaging key biomarkers of tumor angiogenesis. Theranostics 2:502–515
Willam C, Koehne P, Jurgensen JS et al (2000) Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells. Circ Res 87:370–377
Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70
Jeltsch M, Leppanen VM, Saharinen P, Alitalo K (2013) Receptor tyrosine kinase-mediated angiogenesis. Cold Spring Harb Perspect Biol 5. doi:10.1101/cshperspect.a009183
Yancopoulos GD, Davis S, Gale NW et al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248
Jones N, Iljin K, Dumont DJ, Alitalo K (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2:257–267
Alvarez RH, Kantarjian HM, Cortes JE (2006) Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin Proc 81:1241–1257
Tateishi U, Oka T, Inoue T (2012) Radiolabeled RGD peptides as integrin alpha(v)beta3-targeted PET tracers. Curr Med Chem 19:3301–3309
Iagaru A, Gambhir SS (2013) Imaging tumor angiogenesis: the road to clinical utility. AJR Am J Roentgenol 201:W183–W191
Haubner R, Beer AJ, Wang H, Chen X (2010) Positron emission tomography tracers for imaging angiogenesis. Eur J Nucl Med Mol Imaging 37(Suppl 1):S86–S103
Cai W, Niu G, Chen X (2008) Imaging of integrins as biomarkers for tumor angiogenesis. Curr Pharm Des 14:2943–2973
Shyu KG, Chang CC, Wang BW et al (2003) Increased expression of angiopoietin-2 and Tie2 receptor in a rat model of myocardial ischaemia/reperfusion. Clin Sci (Lond) 105:287–294
Shyu KG, Liang YJ, Chang H et al (2004) Enhanced expression of angiopoietin-2 and the Tie2 receptor but not angiopoietin-1 or the Tie1 receptor in a rat model of myocardial infarction. J Biomed Sci 11:163–171
Li J, Brown LF, Hibberd MG, Grossman JD et al (1996) VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 270:H1803–H1811
Hasegawa M, Nishigaki N, Washio Y et al (2007) Discovery of novel benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors. J Med Chem 50:4453–4470
Leopoldo M, Lacivita E, De Giorgio P et al (2008) Structural modifications of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides: influence on lipophilicity and 5-HT7 receptor activity. Part III. J Med Chem 51:5813–5822
Cai L, Chin FT, Pike VW et al (2004) Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4′-N, N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer’s disease. J Med Chem 47:2208–2218
Grass TM, Lurie DI, Coffin JD (2006) Transitional angiogenesis and vascular remodeling during coronary angiogenesis in response to myocardial infarction. Acta Histochem 108:293–302
Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97:512–523
Acknowledgments
The authors wish to thank Sassi Cohen, Daniel Wajnblum, and Nickolay Koroukhov for their invaluable technical support and assistance.
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The authors declare that they have no conflicts of interest.
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Dissoki, S., Abourbeh, G., Salnikov, O. et al. PET Molecular Imaging of Angiogenesis with a Multiple Tyrosine Kinase Receptor-Targeted Agent in a Rat Model of Myocardial Infarction. Mol Imaging Biol 17, 222–230 (2015). https://doi.org/10.1007/s11307-014-0790-8
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DOI: https://doi.org/10.1007/s11307-014-0790-8