We performed a feasibility study to determine the optimal dosage and time of administration of the monoclonal antibody zirconium-89 ((89)Zr)-trastuzumab to enable positron emission tomography (PET) imaging of human epidermal growth factor receptor 2 (HER2)-positive lesions. Fourteen patients with HER2-positive metastatic breast cancer received 37 MBq of (89)Zr-trastuzumab at one of three doses (10 or 50 mg for those who were trastuzumab-naive and 10 mg for those who were already on trastuzumab treatment). The patients underwent at least two PET scans between days 2 and 5. The results of the study showed that the best time for assessment of (89)Zr-trastuzumab uptake by tumors was 4-5 days after the injection. For optimal PET-scan results, trastuzumab-naive patients required a 50 mg dose of (89)Zr-trastuzumab, and patients already on trastuzumab treatment required a 10 mg dose. The accumulation of (89)Zr-trastuzumab in lesions allowed PET imaging of most of the known lesions and some that had been undetected earlier. The relative uptake values (RUVs) (mean +/- SEM) were 12.8 +/- 5.8, 4.1 +/- 1.6, and 3.5 +/- 4.2 in liver, bone, and brain lesions, respectively, and 5.9 +/- 2.4, 2.8 +/- 0.7, 4.0 +/- 0.7, and 0.20 +/- 0.1 in normal liver, spleen, kidneys, and brain tissue, respectively. PET scanning after administration of (89)Zr-trastuzumab at appropriate doses allows visualization and quantification of uptake in HER2-positive lesions in patients with metastatic breast cancer.

This study evaluated the performance of the Biograph Vision digital PET/CT system according to the NEMA NU 2-2012 standard (published by the National Electrical Manufacturers Association [NEMA]) to allow for a reliable, reproducible, and intersystemcomparable performance measurement. Methods: The new digital PET/CT system features silicon photomultiplier-based detectors with 3.2-mm lutetium oxyorthosilicate crystals and full coverage of the scintillator area. The PET components incorporate 8 rings of 38 detector blocks, and each block contains 4 • 2 mini blocks. Each mini block consists of a 5 • 5 lutetium oxyorthosilicate array of 3.2 • 3.2 • 20 mm crystals coupled to a silicon photomultiplier array of 16 • 16 mm, resulting in an axial field of view of 26.1 cm. In this study, PET/CT system performance was evaluated for conformation with the NEMA NU 2-2012 standard, with additional measurements described in the new NEMA NU 2-2018 standard. Spatial resolution, sensitivity, count-rate performance, accuracy of attenuation and scatter correction, image quality, coregistration accuracy, and time-of-flight performance were determined. Measurements were directly compared with results from its predecessor, the Biograph mCT Flow, using existing literature. Moreover, feasibility to comply with the European Association of Nuclear Medicine Research Ltd. (EARL) criteria was evaluated, and some illustrative patient PET images were obtained. Results: The Biograph Vision showed a transverse and axial spatial resolution of 3.6 and 3.5 mm, respectively, in full width at half maximum at a 1-cm offset from the center of the field of view (measured with a 22 Na 0.25-mm point source), a NEMA sensitivity of 16.4 kcps/MBq, and a NEMA peak noise-equivalent count-rate of 306 kcps at 32 kBq/mL. Time-of-flight resolution varied from 210 to 215 as count-rate increased up to the peak noise-equivalent count-rate. The overall image contrast seen with the NEMA image quality phantom ranged from 77.2% to 89.8%. Furthermore, the system was able to comply with the current and future EARL performance criteria. Conclusion: The Biograph Vision outperforms the analog Biograph mCT Flow, and the system is able to meet European harmonizing performance standards.

Vascular endothelial growth factor (VEGF), released by tumor cells, is an important growth factor in tumor angiogenesis. The humanized monoclonal antibody bevacizumab blocks VEGFinduced tumor angiogenesis by binding, thereby neutralizing VEGF. Our aim was to develop radiolabeled bevacizumab for noninvasive in vivo VEGF visualization and quantification with the single g-emitting isotope 111 In and the PET isotope 89 Zr. Methods: Labeling, stability, and binding studies were performed. Nude mice with a human SKOV-3 ovarian tumor xenograft were injected with 89 Zr-bevacizumab, 111 In-bevacizumab, or human 89 Zr-IgG. Human 89 Zr-IgG served as an aspecific control antibody. Small-animal PET and microCT studies were obtained at 24, 72, and 168 h after injection of 89 Zr-bevacizumab and 89 Zr-IgG (3.5 6 0.5 MBq, 100 6 6 mg, 0.2 mL [mean 6 SD]). Small-animal PET and microCT images were fused to calculate tumor uptake and compared with ex vivo biodistribution at 168 h after injection. 89 In-bevacizumab ex vivo biodistribution was compared at 24, 72, and 168 h after injection (2.0 6 0.5 MBq each, 100 6 4 mg in total, 0.2 mL). Results: Labeling efficiencies, radiochemical purity, stability, and binding properties were optimal for the radioimmunoconjugates. Small-animal PET showed uptake in well-perfused organs at 24 h and clear tumor localization from 72 h onward. Tumor uptake determined by quantification of small-animal PET images was higher for 89 Zr-bevacizumab-namely, 7.38 6 2.06 %ID/g compared with 3.39 6 1.16 %ID/g (percentage injected dose per gram) for human 89 Zr-IgG (P 5 0.011) at 168 h and equivalent to ex vivo biodistribution studies. Tracer uptake in other organs was seen primarily in liver and spleen. 89 In-bevacizumab biodistribution was comparable. Conclusion: Radiolabeled bevacizumab showed higher uptake compared with radiolabeled human IgG in a human SKOV-3 ovarian tumor xenograft. Noninvasive quantitative small-animal PET was similar to invasive ex vivo biodistribution. Radiolabeled bevacizumab is a new tracer for noninvasive in vivo imaging of VEGF in the tumor microenvironment.

The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/ neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibodybased therapy, and to support early antibody development. The PET radiopharmaceutical 89 Zr-trastuzumab was compared with the SPECT tracer 111 In-trastuzumab, which we have tested in the clinic already. Methods: Trastuzumab was labeled with 89 Zr and (for comparison) with 111 In. The minimal dose of trastuzumab required for optimal small-animal PET imaging and biodistribution was determined with human HER2/neu-positive or -negative tumor xenograft-bearing mice. Results: Trastuzumab was efficiently radiolabeled with 89 Zr at a high radiochemical purity and specific activity. The antigen-binding capacity was preserved, and the radiopharmaceutical proved to be stable for up to 7 d in solvent and human serum. Of the tested protein doses, the minimal dose of trastuzumab (100 mg) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of 89 Zr-trastuzumab in HER2/neu-positive tumors than in HER2/neu-negative tumors, especially at day 6 (33.4 6 7.6 [mean 6 SEM] vs. 7.1 6 0.7 percentage injected dose per gram of tissue). There were good correlations between the small-animal PET images and the biodistribution data and between 89 In-trastuzumab uptake in tumors (R 2 5 0.972). Conclusion: Clinical-grade 89 Zr-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution.