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A new PET tracer specific for vascular endothelial growth factor receptor 2.
Eur J Nucl Med Mol Imaging. 2007 Dec; 34(12):2001-10.EJ

Abstract

PURPOSE

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).

CONCLUSION

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Evaluation Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

17694307

Citation

Wang, Hui, et al. "A New PET Tracer Specific for Vascular Endothelial Growth Factor Receptor 2." European Journal of Nuclear Medicine and Molecular Imaging, vol. 34, no. 12, 2007, pp. 2001-10.
Wang H, Cai W, Chen K, et al. A new PET tracer specific for vascular endothelial growth factor receptor 2. Eur J Nucl Med Mol Imaging. 2007;34(12):2001-10.
Wang, H., Cai, W., Chen, K., Li, Z. B., Kashefi, A., He, L., & Chen, X. (2007). A new PET tracer specific for vascular endothelial growth factor receptor 2. European Journal of Nuclear Medicine and Molecular Imaging, 34(12), 2001-10.
Wang H, et al. A New PET Tracer Specific for Vascular Endothelial Growth Factor Receptor 2. Eur J Nucl Med Mol Imaging. 2007;34(12):2001-10. PubMed PMID: 17694307.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A new PET tracer specific for vascular endothelial growth factor receptor 2. AU - Wang,Hui, AU - Cai,Weibo, AU - Chen,Kai, AU - Li,Zi-Bo, AU - Kashefi,Amir, AU - He,Lina, AU - Chen,Xiaoyuan, Y1 - 2007/08/11/ PY - 2007/05/22/received PY - 2007/06/30/accepted PY - 2007/8/19/pubmed PY - 2008/6/3/medline PY - 2007/8/19/entrez SP - 2001 EP - 10 JF - European journal of nuclear medicine and molecular imaging JO - Eur J Nucl Med Mol Imaging VL - 34 IS - 12 N2 - PURPOSE: 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). CONCLUSION: 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. SN - 1619-7070 UR - https://www.unboundmedicine.com/medline/citation/17694307/abstract/A_new_PET_tracer_specific_for_vascular_endothelial_growth_factor_receptor_2_ L2 - https://dx.doi.org/10.1007/s00259-007-0524-0 DB - PRIME DP - Unbound Medicine ER -