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  • 1
    Publication Date: 2018-09-05
    Description: One of the most clinically relevant molecular aberrations in breast cancer is overexpression of human epidermal growth factor receptor type 2 (HER2). We aimed to develop a radiolabeled tyrosine kinase inhibitor for HER2-targeted breast cancer imaging. In this study, a radioiodinated analog ( 125/131 I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous human breast cancer xenografts. Methods: The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases. 125/131 I-IBA-CP was prepared using a copper-mediated radioiodination method with enhanced labeling yield and molar activity. In vitro biologic activity, including specific and nonspecific binding of 131 I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animal 125 I-IBA-CP SPECT imaging and biodistribution studies were conducted on mice bearing HER2-positive, HER2-negative, or epidermal growth factor receptor (EGFR)-positive tumors. Nonradioactive IBA-CP and the EGFR inhibitor erlotinib were used as blocking agents to investigate the binding specificity and selectivity of 125/131 I-IBA-CP toward HER2 in vitro and in vivo. Additionally, 125/131 I-ICP was prepared by direct radioiodination of CP724,714 for comparison with 125/131 I-IBA-CP. Results: IBA-CP displayed superior in vitro inhibitory activity (half-maximal inhibitory concentration, 16 nM) and selectivity for HER2 over 6 other cancer-related tyrosine kinases. 125/131 I-IBA-CP was prepared in a typical radiochemical yield of about 65% (decay-corrected), radiochemical purity of more than 98%, and molar activity of 42 GBq/μmol at the end of synthesis. SPECT imaging revealed significantly higher uptake of 125 I-IBA-CP than of 125 I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding of 125 I-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. Conclusion: The radiolabeled HER2-selective inhibitor 125/131 I-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.
    Print ISSN: 0022-3123
    Topics: Medicine
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  • 2
    Publication Date: 2018-12-04
    Description: 18 F-alfatide II has been proven to have excellent clinical translational potential. In this study, we investigated 18 F-alfatide II for identifying breast cancer and compared the performances between 18 F-alfatide II and 18 F-FDG. Methods: Forty-four female patients with suspected primary breast cancer were recruited. PET/CT images using 18 F-alfatide II and 18 F-FDG were acquired within 7 d. Tracer uptake in breast lesions was evaluated by visual analysis, and semiquantitative analysis with SUV max and SUV mean . Results: Forty-two breast cancer lesions and 11 benign breast lesions were confirmed by histopathology in 44 patients. Both 18 F-alfatide II and 18 F-FDG had higher uptake in breast cancer lesions than in benign breast lesions ( P 〈 0.05 for 18 F-alfatide II, P 〈 0.05 for 18 F-FDG). The area under the curve of 18 F-alfatide II was slightly less than that of 18 F-FDG. Both 18 F-alfatide II and 18 F-FDG had high sensitivity (88.1% vs. 90.5%), high positive predictive value (88.1% vs. 88.4%), moderate specificity (54.5% vs. 54.5%), and moderate negative predictive value (54.5% vs. 60.0%) for differentiating breast cancer from benign breast lesions. By combining 18 F-alfatide II and 18 F-FDG, the sensitivity and negative predictive value significantly increased to 97.6% and 85.7%, respectively, with positive predictive value slightly increased to 89.1% and no change to the specificity (54.5%). The uptake of 18 F-alfatide II (SUV max : 3.77 ± 1.78) was significantly lower than that of 18 F-FDG (SUV max : 7.37 ± 4.48) in breast cancer lesions ( P 〈 0.05). 18 F-alfatide II uptake in triple-negative subtype was significantly lower than that in luminal A and luminal B subtypes. By contrast, human epidermal growth factor receptor-2 (HER-2)–overexpressing subtype had higher 18 F-FDG uptake than the other 3 subtypes. There were 8 breast cancer lesions with higher 18 F-alfatide II uptake than 18 F-FDG uptake, which all had a common characteristic that HER-2 expression was negative and estrogen receptor expression was strongly positive. Conclusion: 18 F-alfatide II is suitable for clinical use in breast cancer patients. 18 F-alfatide II is of good performance, but not superior to 18 F-FDG in identifying breast cancer. 18 F-alfatide II may have superiority to 18 F-FDG in detecting breast cancer with strongly positive estrogen receptor expression and negative HER-2 expression.
    Print ISSN: 0022-3123
    Topics: Medicine
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  • 3
    Publication Date: 2018-03-06
    Description: We characterize a compact MR-compatible PET insert for simultaneous preclinical PET/MRI. Although specifically designed with the strict size constraint to fit inside the 114-mm inner diameter of the BGA-12S gradient coil used in the BioSpec 70/20 and 94/20 series of small-animal MRI systems, the insert can easily be installed in any appropriate MRI scanner or used as a stand-alone PET system. Methods: The insert consists of a ring of 16 detector-blocks each made from depth-of-interaction–capable dual-layer-offset arrays of cerium-doped lutetium-yttrium oxyorthosilicate crystals read out by silicon photomultiplier arrays. Scintillator crystal arrays are made from 22 x 10 and 21 x 9 crystals in the bottom and top layers, respectively, with respective layer thicknesses of 6 and 4 mm, arranged with a 1.27-mm pitch, resulting in a useable field of view 28 mm long and about 55 mm wide. Results: Spatial resolution ranged from 1.17 to 1.86 mm full width at half maximum in the radial direction from a radial offset of 0–15 mm. With a 300- to 800-keV energy window, peak sensitivity was 2.2% and noise-equivalent count rate from a mouse-sized phantom at 3.7 MBq was 11.1 kcps and peaked at 20.8 kcps at 14.5 MBq. Phantom imaging showed that features as small as 0.7 mm could be resolved. 18 F-FDG PET/MR images of mouse and rat brains showed no signs of intermodality interference and could excellently resolve substructures within the brain. Conclusion: Because of excellent spatial resolvability and lack of intermodality interference, this PET insert will serve as a useful tool for preclinical PET/MR.
    Print ISSN: 0022-3123
    Topics: Medicine
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  • 4
    Publication Date: 2018-06-02
    Description: We describe a long axial field-of-view (FOV) PET scanner for high-sensitivity and total-body imaging of nonhuman primates and present the physical performance and first phantom and animal imaging results. Methods: The mini-EXPLORER PET scanner was built using the components of a clinical scanner reconfigured with a detector ring diameter of 43.5 cm and an axial length of 45.7 cm. National Electrical Manufacturers Association (NEMA) NU-2 and NU-4 phantoms were used to measure sensitivity and count rate performance. Reconstructed spatial resolution was investigated by imaging a radially stepped point source and a Derenzo phantom. The effect of the wide acceptance angle was investigated by comparing performance with maximum acceptance angles of 14°–46°. Lastly, an initial assessment of the in vivo performance of the mini-EXPLORER was undertaken with a dynamic 18 F-FDG nonhuman primate (rhesus monkey) imaging study. Results: The NU-2 total sensitivity was 5.0%, and the peak noise-equivalent count rate measured with the NU-4 monkey scatter phantom was 1,741 kcps, both obtained using the maximum acceptance angle (46°). The NU-4 scatter fraction was 16.5%, less than 1% higher than with a 14° acceptance angle. The reconstructed spatial resolution was approximately 3.0 mm at the center of the FOV, with a minor loss in axial spatial resolution (0.5 mm) when the acceptance angle increased from 14° to 46°. The rhesus monkey 18 F-FDG study demonstrated the benefit of the high sensitivity of the mini-EXPLORER, including fast imaging (1-s early frames), excellent image quality (30-s and 5-min frames), and late-time-point imaging (18 h after injection), all obtained at a single bed position that captured the major organs of the rhesus monkey. Conclusion: This study demonstrated the physical performance and imaging capabilities of a long axial FOV PET scanner designed for high-sensitivity imaging of nonhuman primates. Further, the results of this study suggest that a wide acceptance angle can be used with a long axial FOV scanner to maximize sensitivity while introducing only minor trade-offs such as a small increase in scatter fraction and slightly degraded axial spatial resolution.
    Print ISSN: 0022-3123
    Topics: Medicine
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