64Cu-1,4,7,10-Tetraazacyclodecane-N,N',N'',N'''-tetraacetic acid (DOTA)-vascular endothelial growth factor (64Cu-DOTA-VEGF) is a radiolabeled molecular imaging agent developed for positron emission tomography (PET) imaging of tumor angiogenesis and guiding antiangiogenic treatment (1). 64Cu is a positron emitter with a half-life (t½) of 12.7 h.
Angiogenesis is a process of development and growth of new blood vessels from pre-existing vessels (2). Tumor growth depends on the formation of new blood vessels from this process. Normal angiogenesis is orderly and highly regulated, whereas tumor angiogenesis is chaotic and irregular. Abnormal angiogenesis is important in the carcinogenesis, growth and progression of human solid and hematologic tumors (3). VEGF is both a vascular growth factor and a vascular permeability factor, and it plays a central and critical role in the regulation of angiogenesis (4). VEGF induces proliferation, sprouting, migration, and tube formation of endothelial cells (5). Different forms of VEGF bind to receptors that exhibit a tyrosine-kinase activity (2). VEGF and VEGF receptors (VEGFR) have been shown to be upregulated in many tumors.
VEGF is a dimeric glycoprotein of 36−46 kDa that has been implicated in several steps throughout the process of angiogenesis (3). The VEGF family currently consists of 6 growth factors and 3 high-affinity tyrosine-kinase receptors. The specific action of VEGF on the endothelial cells is mainly regulated by VEGFR1 and VEGFR2 (2). VEGF-A is the most well characterized member of the VEGF family and is composed of at least 7 isoforms due to alternative gene splicing. Located at chromosome 6p21.3, VEGF-A is encoded by 8 exons separated by 7 introns. These forms differ mainly in their bioavailability and can be characterized by heparin and heparin-sulfate binding domains encoded by exons 6 and 7. VEGF121 (121 amino acids) and VEGF165 (165 amino acids) isoforms have been shown to induce mitogenic and permeability-enhancing activity on endothelial cells. VEGF gene expression is upregulated by many stimuli and hormones. In cancer, VEGF is upregulated by the genetic events leading to malignant transformation. VEGF and its receptors are overexpressed in a variety of solid tumors (1).
Molecular imaging of angiogenesis offers serial non-invasive evaluation of various tumor parameters (6) PET imaging with the appropriate radiolabeled tracer targeted to angiogenic signaling pathways may allow the evaluation of specific aspects of tumor vascular biology. VEGF has been labeled with 111In, 123I and 99mTc as potential Single Photon Emission Tomography imaging agents (7). Cai et al. (1) prepared the first PET agent for imaging VEGF by labeling VEGF121 with 64Cu.