title: Variation of Specific Activities of 68Ga-Aquibeprin and 68Ga-Avebetrin Enables Selective PET Imaging of Different Expression Levels of Integrins α5β1 and αvβ3.
abstract: 68Ga-aquibeprin and68Ga-avebetrin are tracers for selective in vivo mapping of integrins α5β1and αvβ3, respectively, by PET. Because both tracers exhibit high affinity to their respective targets, the aim of this study was to investigate the influence of the specific activity of preparations of both tracers on in vivo imaging results.
  
  
  METHODS
  Fully automated68Ga labeling of 0.3 nmol of aquibeprin or avebetrin was done using buffered eluate fractions (600-800 MBq, pH 2) of an SnO2-based generator, affording the radiopharmaceuticals with specific activities greater than 1,000 MBq/nmol. Lower values ranging from 150 to 0.4 MBq/nmol were adjusted by addition of inactive compound (∼0.15-50 nmol) to the injected activity (∼20 MBq for PET, 5-7 MBq for biodistribution). For in vivo experiments, 6- to 12-wk-old female severe combined immunodeficiency mice bearing M21 xenografts (human melanoma, expressing both integrins α5β1and αvβ3) were used. The expression density of integrin β3was determined by immunohistochemistry on paraffin slices.
  
  
  RESULTS
  For mass doses (specific activities) of less than 20 pmol (>1,000 MBq/nmol) and 1 nmol (20 MBq/nmol) per mouse, respectively, uptake of68Ga-aquibeprin and68Ga-avebetrin in M21 tumors dropped from 5.3 and 3.5 to 3.0 and 2.4 percentage injected dose per gram (%ID/g), respectively. When less than 20 pmol was applied, high uptake of68Ga-aquibeprin in the eyes (4.5 %ID/g) or68Ga-avebetrin in adrenals (25.9 %ID/g), respectively, were found, which was reduced by 90% and 65% (0.44 and 6.2 %ID/g, respectively), for doses of 1 nmol. The highest tumor-to-tissue ratios were observed both in ex vivo biodistribution and PET for comparably large doses, for example, 6 nmol (0.65 mg/kg)68Ga-aquibeprin per mouse (3.5 MBq/nmol).
  
  
  CONCLUSIONS
  Presumably because of their high affinities,68Ga-aquibeprin and68Ga-avebetrin allow for selective addressing of target sites with different integrin expression levels by virtue of adjusting specific activity, which can be exploited for visualization of low-level target expression or optimization of tumor-to-background contrast.
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany johannes.notni@tum.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Notni
authors.affiliation: Institute of Pathology, Technische Universität München, Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Hoffmann
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Reich
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Institute for Advanced Study and Center of Integrated Protein Science, Department Chemie, Technische Universität München, Munich, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D014018:Tissue Distribution
chemical_list: C000609145:68Ga-aquibeprin; C000609146:68Ga-avebetrin; D056831:Coordination Complexes; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3
keywords: 68Ga; positron emission tomography; preclinical imaging; receptor density