title: In vivo imaging of Aminopeptidase N (CD13) receptors in experimental renal tumors using the novel radiotracer (68)Ga-NOTA-c(NGR).
abstract: OBJECTIVE
  Aminopeptidase N (APN/CD13) plays an important role in tumor neoangiogenic process and the development of metastases. Furthermore, it may serve as a potential target for cancer diagnosis and therapy. Previous studies have already shown that asparagine-glycine-arginine (NGR) peptides specifically bind to APN/CD13. The aim of the study was to synthesize and investigate the APN/CD13 specificity of a novel (68)Ga-labeled NOTA-c(NGR) molecule in vivo using miniPET.
  
  
  METHODS
  c[KNGRE]-NH2 peptide was conjugated with p-SCN-Bn-NOTA and was labeled with Ga-68 ((68)Ga-NOTA-c(NGR)). Orthotopic and heterotopic transplanted mesoblastic nephroma (NeDe) bearing Fischer-344 rats were prepared, on which biodistribution studies and miniPET scans were performed for both (68)Ga-NOTA-c(NGR) and ανβ3 integrin selective (68)Ga-NODAGA-[c(RGD)]2 tracers. APN/CD13 receptor expression of NeDe tumors and metastases was analyzed by western blot.
  
  
  RESULTS
  (68)Ga-NOTA-c(NGR) was produced with high specific activity (5.13-5.92GBq/μmol) and with excellent radiochemical purity (95%<), at all cases. Biodistribution studies in normal rats showed that uptake of the (68)Ga-NOTA-c(NGR) was significantly (p⩽0.05) lower in abdominal organs in comparison with (68)Ga-NODAGA-[c(RGD)]2. Both radiotracers were mainly excreted from the kidney. In NeDe tumor bearing rats higher (68)Ga-NOTA-c(NGR) accumulation was found in the tumors than that of the (68)Ga-NODAGA-[c(RGD)]2. Using orthotopic transplantation, metastases were developed which showed specific (68)Ga-NOTA-c(NGR) uptake. Western blot analysis confirmed the presence of APN/CD13 expression in NeDe tumors and metastases.
  
  
  CONCLUSIONS
  Our novel radiotracer (68)Ga-NOTA-c(NGR) showed specific binding to the APN/CD13 expressed ortho- and heterotopic transplanted NeDe tumors. Therefore, (68)Ga-NOTA-c(NGR) is a suitable tracer for the detection of APN/CD13 positive tumors and metastases in vivo.
authors.affiliation: Department of Nuclear Medicine, University of Debrecen, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Máté
authors.affiliation: Department of Nuclear Medicine, University of Debrecen, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Kertész
authors.affiliation: MTA-ELTE, Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary.
authors.forename: Kata Nóra
authors.initials: KN
authors.lastname: Enyedi
authors.affiliation: MTA-ELTE, Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Mező
authors.affiliation: Department of Periodontology, University of Debrecen, Debrecen, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Angyal
authors.affiliation: Department of Physiology, University of Debrecen, Debrecen, Hungary.
authors.forename: Nikolett
authors.initials: N
authors.lastname: Vasas
authors.affiliation: Department of Nuclear Medicine, University of Debrecen, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kis
authors.affiliation: Department of Periodontology, University of Debrecen, Debrecen, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Szabó
authors.affiliation: Department of Nuclear Medicine, University of Debrecen, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Emri
authors.affiliation: Department of Physiology, University of Debrecen, Debrecen, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Bíró
authors.affiliation: Department of Nuclear Medicine, University of Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Galuska
authors.affiliation: Department of Nuclear Medicine, University of Debrecen, Hungary; Scanomed LTD, Debrecen, Hungary. Electronic address: trencsenyi.gyorgy@med.unideb.hu.
authors.forename: György
authors.initials: G
authors.lastname: Trencsényi
mesh_terms: D000818:Animals; D018826:CD13 Antigens / Q000378:metabolism*; D056831:Coordination Complexes / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010456:Peptides, Cyclic / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: C561299:68Ga-NODAGA-RGD; C000602452:68Ga-NOTA-c(NGR); D056831:Coordination Complexes; D010456:Peptides, Cyclic; D011849:Radioactive Tracers; D018826:CD13 Antigens
keywords: (68)Ga-NODAGA-[c(RGD)](2); (68)Ga-NOTA-c(NGR); (Benzotriazol-1-yloxy)tris(dimethylamino) phosphonium; 1-Hydroxybenzotriazole (HOBt) (PubChem CID: 2796029); 14,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) (PubChem CID: 3036142); Aminopeptidase N (CD13) expression; Dimethylformamide (DMF) (PubChem CID: 6228); Glyicine (PubChem CID: 750); Hexafluorophosphate (PubChem CID: 151348); N-diisopropylethylamine (DIEA) (PubChem CID: 81531); Positron emission tomography; Renal tumors; Trifluoroacetic acid (TFA) (PubChem CID: 6422); Triisopropylsilane (TIS) (PubChem CID: 6327611); Tumor angiogenesis; l-Arginine (PubChem CID: 6322); l-Asparagine (PubChem CID: 6267); l-Glutamic acid (PubChem CID: 33032); l-Lysine (PubChem CID: 5962)