Johannes Notni1, Katja Steiger2, Frauke Hoffmann3, Dominik Reich3, Markus Schwaiger4, Horst Kessler5, Hans-Jürgen Wester3. 1. Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany johannes.notni@tum.de. 2. Institute of Pathology, Technische Universität München, Munich, Germany. 3. Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany. 4. Department of Nuclear Medicine, Technische Universität München, Munich, Germany; and. 5. Institute for Advanced Study and Center of Integrated Protein Science, Department Chemie, Technische Universität München, Munich, Germany.
Abstract
68Ga-aquibeprin and 68Ga-avebetrin are tracers for selective in vivo mapping of integrins α5β1 and 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 automated 68Ga 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 α5β1 and αvβ3) were used. The expression density of integrin β3 was 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 of 68Ga-aquibeprin and 68Ga-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 of 68Ga-aquibeprin in the eyes (4.5 %ID/g) or 68Ga-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). CONCLUSION: Presumably because of their high affinities, 68Ga-aquibeprin and 68Ga-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.
68Ga-aquibeprin and 68Ga-avebetrin are tracers for selective in vivo mapping of integrins α5β1 and 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 automated 68Ga 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 immunodeficiencymice bearing M21 xenografts (humanmelanoma, expressing both integrins α5β1 and αvβ3) were used. The expression density of integrin β3 was 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 of 68Ga-aquibeprin and 68Ga-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 of 68Ga-aquibeprin in the eyes (4.5 %ID/g) or 68Ga-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). CONCLUSION: Presumably because of their high affinities, 68Ga-aquibeprin and 68Ga-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: Federica Pisaneschi; Lindsay E Kelderhouse; Amanda Hardy; Brian J Engel; Uday Mukhopadhyay; Carlos Gonzalez-Lepera; Joshua P Gray; Argentina Ornelas; Terry T Takahashi; Richard W Roberts; Stephen V Fiacco; David Piwnica-Worms; Steven W Millward Journal: Bioconjug Chem Date: 2017-02-02 Impact factor: 4.774
Authors: Alexander Wurzer; Christof Seidl; Alfred Morgenstern; Frank Bruchertseifer; Markus Schwaiger; Hans-Jürgen Wester; Johannes Notni Journal: Chemistry Date: 2017-09-14 Impact factor: 5.236
Authors: Simone Maschauer; Jürgen Einsiedel; Dominik Reich; Harald Hübner; Peter Gmeiner; Hans-Jürgen Wester; Olaf Prante; Johannes Notni Journal: Pharmaceuticals (Basel) Date: 2017-03-10
Authors: Johannes Notni; Florian T Gassert; Katja Steiger; Peter Sommer; Wilko Weichert; Ernst J Rummeny; Markus Schwaiger; Horst Kessler; Reinhard Meier; Melanie A Kimm Journal: EJNMMI Res Date: 2019-09-09 Impact factor: 3.138