In vivo assessment of aminopeptidase N (APN/CD13) specificity of different 68Galabelled NGR derivatives using PET/MRI imaging

Kis, Adrienn and Dénes, Noémi and Szabó P, Judit and Arató, Viktória and Jószai, István and Enyedi, Kata Nóra and Lakatos, Szilvia and Garai, Ildikó and Mező, Gábor and Kertész, István and Trencsényi, György (2020) In vivo assessment of aminopeptidase N (APN/CD13) specificity of different 68Galabelled NGR derivatives using PET/MRI imaging. INTERNATIONAL JOURNAL OF PHARMACEUTICS, 589. p. 119881. ISSN 0378-5173

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Abstract

Aminopeptidase N (APN/CD13) plays an important role in neoangiogenic process in malignancies. Our previous studies have already shown that 68Ga-labelled NOTA conjugated asparagine-glycine-arginine peptide (c[KNGRE]-NH2) specifically bind to APN/CD13 expressing tumors. The aim of this study was to evaluate and compare the APN/CD13 specificity of newly synthesized 68Ga-labelled NGR derivatives in vivo by PET/MRI imaging using hepatocellular carcinoma (He/De) and mesoblastic nephroma (Ne/De) tumor models. PET/MRI and ex vivo biodistribution studies were performed 11±1 days after subcutaneous injection of tumor cells and 90 min after intravenous injection of 68Ga-NOTA-c(NGR), 68Ga-NODAGA-c(NGR), 68Ga-NODAGA-c(NGR) (MG1) or 68Ga-NODAGA-c(NGR) (MG2). The APN/CD13 selectivity was confirmed by blocking experiments and the APN/CD13 expression was verified by immunohistochemistry. 68Ga-labelled c(NGR) derivatives were produced with high specific activity and radiochemical purity. In control animals, low radiotracer accumulation was found in abdominal and thoracic organs. Using tumor-bearing animals we found that the 68Ga-NOTA-c(NGR), 68Ga-NODAGA-c(NGR), and 68Ga-NODAGA-c(NGR) (MG1) derivatives showed higher uptake in He/De and Ne/De tumors, than that of the accumulation of 68Ga-NODAGA-c(NGR) (MG2). APN/CD13 is a very promising target in PET imaging, however, the selection of the appropriate 68Ga-labelled NGR-based radiopharmaceutical is critical for the precise detection of tumor neoangiogenesis and for monitoring the efficacy of anticancer therapy.

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