PT - JOURNAL ARTICLE AU - Zhang, Yin AU - Hong, Hao AU - Niu, Gang AU - Chen, Xiaoyuan AU - Barnhart, Todd AU - Cai, Weibo TI - PET of VEGFR expression with <sup>61</sup>Cu-labeled lysine-tagged VEGF<sub>121</sub> DP - 2013 May 01 TA - Journal of Nuclear Medicine PG - 111--111 VI - 54 IP - supplement 2 4099 - http://jnm.snmjournals.org/content/54/supplement_2/111.short 4100 - http://jnm.snmjournals.org/content/54/supplement_2/111.full SO - J Nucl Med2013 May 01; 54 AB - 111 Objectives Overexpression of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) indicates poor prognosis in many tumor types. Our goal is to develop a VEGFR-targeted positron emission tomography (PET) tracer based on VEGF121, with three lysine residues fused to the N-terminus (denoted as K3-VEGF121), which can facilitate radiolabeling without affecting its VEGFR binding affinity. 61Cu (t1/2: 3.3 h; 62% β+) was used as the radiolabel to match its uptake kinetics and minimize radiation dosimetry. Methods Purified K3-VEGF121 was conjugated to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and labeled with 61Cu. Cell binding assay was performed to compare the VEGFR-2 binding affinity of K3-VEGF121 and NOTA-K3-VEGF121. PET imaging, biodistribution, blocking, and histology studies were carried out in 4T1 murine breast tumor-bearing mice to evaluate the tumor targeting efficacy and in vivo specificity of 61Cu-NOTA-K3-VEGF121. Radiation dosimetry was extrapolated to humans as well. Results Based on cell binding assay using 125I-VEGF165 as the radioligand, the IC50 values of NOTA-K3-VEGF121 and K3-VEGF121 were comparable to VEGF121 (~ 1 nM). 61Cu labeling was achieved with good yield (&gt; 50 %) and specific activity. Serial PET imaging showed that the 4T1 tumor uptake of 61Cu-NOTA-K3-VEGF121 was 3.4±0.5, 4.9±1.0, 5.2±1.0, and 4.8±0.8 %ID/g (n = 4) at 0.5, 2, 4, and 8 h post-injection respectively, consistent with biodistribution data measured by γ counting. Blocking and histology experiments confirmed VEGFR specificity of 61Cu-NOTA-K3-VEGF121. Dosimetry calculation showed that the radiation dose was much lower than other VEGF-based tracers. Conclusions Successful PET imaging of VEGFR expression was achieved with 61Cu-NOTA-K3-VEGF121, which retained high affinity to VEGFR and exhibited desirable radiation dosimetry. The use of 61Cu is optimal for small proteins like K3-VEGF121, which has higher β+ branching ratio than 64Cu (62% vs. 17%). Thus, it can offer stronger signal intensity and require lower tracer dose for PET imaging than 64Cu, which is ideal for clinical translation.