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M. Simpson 1 , G. Lappin 2 , C. Wagner 3 , O.Langer 3 , I. Morris 4

Combination of accelerator mass spectrometry (AMS) with positron emission tomography (PET) in human microdosing studies. M. Simpson 1 , G. Lappin 2 , C. Wagner 3 , O.Langer 3 , I. Morris 4 1 University of York, York, UK 2 Xceleron Inc, Gaithersburg, MD, USA

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M. Simpson 1 , G. Lappin 2 , C. Wagner 3 , O.Langer 3 , I. Morris 4

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  1. Combination of accelerator mass spectrometry (AMS) with positron emission tomography (PET) in human microdosing studies M. Simpson1, G. Lappin2, C. Wagner3, O.Langer3, I. Morris4 1University of York, York, UK 2Xceleron Inc, Gaithersburg, MD, USA 3Medical University of Vienna, Vienna, Austria 4Hull York Medical School, York, UK

  2. Overview • Accelerator Mass Spectrometry • Positron Emission Tomography • Combining AMS/PET • Clinical Design • AMS/PET Data Summary • Conclusions/Applications

  3. Accelerator Mass Spectrometry • Isotope ratio technique • Originally developed for radiocarbon dating • Extremely sensitive • Typically used with 12C/14C

  4. Accelerator Mass Spectrometry Injection magnet Ion source Linearaccelerator High energyallows separationof rare 14C fromother isotopes 99.8% 12C Analysingmagnet 1.1% 13C 10-11% 14C

  5. Positron Emission Tomography • PET • Non-invasive nuclear imaging technique • Tissue distribution • Drug labelled with positron emitting radionuclide (e.g. 11C or 18F)

  6. Positron Emission Tomography • 11C 11B + β+ + v + energy (97keV) • PET Camera  β+  • 11C • PET Camera

  7. AMS & PET • AMS • Prolonged PK data • Limitation – no distribution information • PET • PK in tissue • Limitation – short term PK only • Combination • Long term PK (AMS) • Brain PK (PET) IN THE SAME SUBJECTS

  8. Clinical Design • Administration of verapamil • Calcium channel inhibitor • P-glycoprotein substrate, crosses blood-brain-barrier • Well documented safety and PK profile • IV dual labelled (R/S)-[14C], (R)-[11C] verapamil (50 µg) Position of dual label (11C and 14C) Chiral centre

  9. Clinical Design (2) IV dual-labelled verapamil (50 μg) IV dual-labelled verapamil (50 μg) Oral verapamil (80 mg) Period 1 Period 2 IV Verapamil = 50 µg(R/S)-[14C] (4.1kBq), (R)-[11C] (407 MBq) • PET scan/arterial plasma collection (0-60 minutes) • Venous plasma collection (0-24 hours) • MRI scan 7 healthy male volunteers 7 healthy male volunteers

  10. Aims • To establish a protocol for microdosing studies • R-verapamil in brain by PET • R- and S-verapamil in plasma by AMS • Assess PK linearity between therapeutic dose and microdose

  11. Quantification of R- and S-verapamil by HPLC-AMS • Separation of R- & S-verapamil by 2D C18-chiral HPLC R-verapamil S-verapamil

  12. Plasma Data Summary R-verapamil Microdose + therapeutic dose Microdose

  13. Plasma PK Data Summary

  14. PET Data Summary PET micro dose PET therapeutic dose MRI SUV 2.8 0

  15. PET Data Summary Total 11C 11C-R-verapamil Arterial plasma Whole brain grey matter

  16. PET Data Summary

  17. Conclusions • Principle of AMS/PET combination demonstrated • Long term plasma PK obtained along with tissue distribution information • Verapamil shown to be dose linear • Plasma (by AMS) • Brain (by PET) • S-verapamil shows preferential clearance • Proof of concept for combination studies • Applications in brain, tumour, cardiac therapy

  18. Acknowledgements PET team - Medical University of Vienna University of York Xceleron Ltd

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