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Preparing a <sup>68</sup>Ga-labeled Arginine Glycine Aspartate (RGD)-peptide for Angiogenesis

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Korea Institute of Radiological and Medical Sciences

The purpose of this study was to develop Cu-labeled trastuzumab with improved pharmacokinetics for human epidermal growth factor receptor 2 (HER2).  Trastuzumab was conjugated with SCN-Bn-NOTA and radiolabeled with Cu. Serum stability and immunoreactivity of Cu-NOTA-trastuzumab were tested. Small-animal PET imaging and biodistribution studies were performed in a HER2-positive breast cancer xenograft model (BT-474). The internal dosimetry for experimental animals was determined using the image-based approach with the Monte Carlo N-particle code. Cu-NOTA-trastuzumab was prepared with high radiolabeling yield and radiochemical purity (>98%) and showed high stability in serum and good immunoreactivity. Uptake of Cu-NOTA-trastuzumab was highest at 48 h after injection as determined by PET imaging and biodistribution results in BT-474 tumors. The blood radioactivity concentrations of Cu-NOTA-trastuzumab decreased biexponentially with time in both mice with and mice without BT-474 tumor xenografts. The calculated absorbed dose of Cu-NOTA-trastuzumab was 0.048 mGy/MBq for the heart, 0.079 mGy/MBq for the liver, and 0.047 mGy/MBq for the spleen. Cu-NOTA-trastuzumab was effectively targeted to the HER2-expressing tumor in vitro and in vivo, and it exhibited a relatively low absorbed dose due to a short residence time. Therefore, Cu-NOTA-trastuzumab could be applied to select the right patients and right timing for HER2 therapy, to monitor the treatment response after HER2-targeted therapy, and to detect distal or metastatic spread.

Development of Cu-NOTA-Trastuzumab for HER2 Targeting: A Radiopharmaceutical with Improved Pharmacokinetics for Human Studies.

Global and regional sympathetic activity in the heart can be evaluated using [I]meta-iodobenzylguanidine ([I]mIBG) imaging. However, [I]mIBG is associated with low image spatial resolution and sensitivity in cardiac imaging. We investigated the capability of an F-18-labeled mIBG derivative, meta-(3-[F]fluoropropyl)benzylguanidine ([F]mFPBG), for identifying ischemic and viable myocardium in a rat model of myocardial infarction.

Feasibility of myocardial PET imaging using a benzylguanidine analog: meta-(3-[F]fluoropropyl)benzylguanidine ([F]mFPBG).

Although amyloid beta (Aβ) imaging is widely used for diagnosing and monitoring Alzheimer's disease in clinical fields, paralleling comparison between F-flutemetamol and F-florbetaben was rarely attempted in AD mouse model. We performed a comparison of Aβ PET images between F-flutemetamol and F-florbetaben in a recently developed APPswe mouse model, C57BL/6-Tg (NSE-hAPPsw) Korl.

Assessment of brain beta-amyloid deposition in transgenic mouse models of Alzheimer's disease with PET imaging agents F-flutemetamol and F-florbetaben.

Epidermal growth factor receptor (EGFR) is overexpressed and considered as a proper molecular target for diagnosis and targeted therapy of esophageal squamous cell carcinoma (ESCC). This study evaluated the usefulness of PET imaging biomarkers with Cu-PCTA-cetuximab and F-FDG-PET for anti-EGFR immunotherapy in ESCC models.  EGFR status and glucose metabolism by cetuximab treatment were evaluated using Cu-PCTA-cetuximab and F-FDG-PET, respectively. Therapeutic responses with imaging biomarkers were confirmed by western blot and immunohistochemistry. TE-4 and TE-8 tumors were clearly visualized by Cu-PCTA-cetuximab, and EGFR expression on TE-8 tumors showed 2.6-fold higher uptake than TE-4. Tumor volumes were markedly reduced by cetuximab in TE-8 tumor (92.5 ± 5.9%), but TE-4 tumors were refractory to cetuximab treatment. The SUVs in Cu-PCTA-cetuximab and F-FDG-PET images were statistically significantly reduced by cetuximab treatment in TE-8 but not in TE-4. Cu-PCTA-cetuximab and F-FDG-PET images were well correlated with EGFR and pAkt levels. Cu-PCTA-cetuximab immuno-PET had a potential for determining EGFR level and monitoring therapeutic response by anti-EGFR therapy. F-FDG-PET was also attractive for monitoring efficacy of anti-EGFR therapy. In conclusion, PET imaging biomarkers may be useful for selecting patients that express target molecules and for monitoring therapeutic efficacy of EGFR-targeted therapy in ESCC patients.

Article	Year
Development of Cu-NOTA-Trastuzumab for HER2 Targeting: A Radiopharmaceutical with Improved Pharmacokinetics for Human Studies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine\| PubMed ID: 29777007	2019
Feasibility of myocardial PET imaging using a benzylguanidine analog: meta-(3-[F]fluoropropyl)benzylguanidine ([F]mFPBG). Nuclear medicine and biology\| PubMed ID: 29783202	2018
Assessment of brain beta-amyloid deposition in transgenic mouse models of Alzheimer's disease with PET imaging agents F-flutemetamol and F-florbetaben. BMC neuroscience\| PubMed ID: 30053803	2018
PET Imaging Biomarkers of Anti-EGFR Immunotherapy in Esophageal Squamous Cell Carcinoma Models. Cells\| PubMed ID: 30373221	2018

Yong Jin Lee

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