title: [68Ga]NODAGA-RGD for imaging αvβ3 integrin expression.
abstract: OBJECTIVE
  A molecular target involved in the angiogenic process is the α(v)β(3) integrin. It has been demonstrated in preclinical as well as in clinical studies that radiolabelled RGD peptides and positron emission tomography (PET) allow noninvasive monitoring of α(v)β(3) expression. Here we introduce a (68)Ga-labelled NOTA-conjugated RGD peptide ([(68)Ga]NODAGA-RGD) and compare its imaging properties with [(68)Ga]DOTA-RGD using small animal PET.
  
  
  METHODS
  Synthesis of c(RGDfK(NODAGA)) was based on solid phase peptide synthesis protocols using the Fmoc strategy. The (68)Ga labelling protocol was optimized concerning temperature, peptide concentration and reaction time. For in vitro characterization, partition coefficient, protein binding properties, serum stability, α(v)β(3) binding affinity and cell uptake were determined. To characterize the in vivo properties, biodistribution studies and microPET imaging were carried out. For both in vitro and in vivo evaluation, α(v)β(3)-positive human melanoma M21 and α(v)β(3)-negative M21-L cells were used.
  
  
  RESULTS
  [(68)Ga]NODAGA-RGD can be produced within 5 min at room temperature with high radiochemical yield and purity (> 96%). In vitro evaluation showed high α(v)β(3) binding affinity (IC(50) = 4.7 ± 1.6 nM) and receptor-specific uptake. The radiotracer was stable in phosphate-buffered saline, pH 7.4, FeCl(3) solution, and human serum. Protein-bound activity after 180 min incubation was found to be 12-fold lower than for [(68)Ga]DOTA-RGD. Biodistribution data 60 min post-injection confirmed receptor-specific tumour accumulation. The activity concentration of [(68)Ga]NODAGA-RGD was lower than [(68)Ga]DOTA-RGD in all organs and tissues investigated, leading to an improved tumour to blood ratio ([(68)Ga]NODAGA-RGD: 11, [(68)Ga]DOTA-RGD: 4). MicroPET imaging confirmed the improved imaging properties of [(68)Ga]NODAGA-RGD compared to [(68)Ga]DOTA-RGD.
  
  
  CONCLUSIONS
  The introduced [(68)Ga]NODAGA-RGD combines easy accessibility with high stability and good imaging properties making it an interesting alternative to the (18)F-labelled RGD peptides currently used for imaging α(v)β(3) expression.
authors.affiliation: Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria. peter.knetsch@i-med.ac.at
authors.forename: Peter A
authors.initials: PA
authors.lastname: Knetsch
authors.forename: Milos
authors.initials: M
authors.lastname: Petrik
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Griessinger
authors.forename: Christine
authors.initials: C
authors.lastname: Rangger
authors.forename: Melpomeni
authors.initials: M
authors.lastname: Fani
authors.forename: Christian
authors.initials: C
authors.lastname: Kesenheimer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: von Guggenberg
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Irene
authors.initials: I
authors.lastname: Virgolini
authors.forename: Clemens
authors.initials: C
authors.lastname: Decristoforo
authors.forename: Roland
authors.initials: R
authors.lastname: Haubner
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000493:pharmacokinetics; D005786:Gene Expression Regulation; D006571:Heterocyclic Compounds / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007553:Isotope Labeling; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: C561299:68Ga-NODAGA-RGD; D056831:Coordination Complexes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010456:Peptides, Cyclic; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; C047981:arginyl-glycyl-aspartic acid