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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 3 Medical University.

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Presentation on theme: "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 3 Medical University."— Presentation transcript:

1 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 3 Medical University of Vienna, Vienna, Austria 4 Hull 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 12 C/ 14 C

4 Accelerator Mass Spectrometry Ion source Injection magnet Linear accelerator Analysing magnet 12 C 13 C 14 C High energy allows separation of rare 14 C from other isotopes 99.8% 1.1% %

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

6 Positron Emission Tomography PET Camera 11 C 11 B + β + + v + energy (97keV) β+β+ 11 C 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)-[ 14 C], (R)-[ 11 C] verapamil (50 µg) Chiral centre Position of dual label ( 11 C and 14 C)

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

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 Microdose + therapeutic dose

13 Plasma PK Data Summary ParameterEnantiomerMicrodose Microdose + therapeutic dose t 1/2 (h) R 6.3 ± ±1.6 S 7.2 ± ±2.2 C max (pg/mL) R ± ±77.7 S 96.3 ± ±33.6 AUC (0-24) (h pg/mL) R ± ±265.1 S ± ±59.7 AUC (0-inf) (h pg/mL) R ± ±281.1 S ± ±58.9 CL (L/h) R 61.0 ± ±10.9 S 89.7 ± ±14.7 V (L) R ± ±133.0 S ± ±272.8 V ss (L) R ± ±68.7 S682.0 ± ±187.6

14 PET Data Summary SUV PET therapeutic dosePET micro doseMRI 2.8 0

15 PET Data Summary Arterial plasmaWhole brain grey matter Total 11 C 11 C-R-verapamil

16 PET Data Summary ParameterMicrodose Microdose + therapeutic dose K 1 (mL mL -1 min -1 ) 0.030±0.003 (10)0.031±0.005 (8) k 2 (min -1 )0.099±0.006 (49)0.095±0.008 (40) k 3 (min -1 ) k 4 (min -1 ) 0.100±0.001 (90) 0.092±0.029 (26) 0.101±0.000 (96) 0.159±0.063 (42) DV (mL mL -1 ) 0.66±0.12 (4)0.56±0.11 (2) DV (Logan) (mL mL -1 ) 0.66±0.11 (2)0.57±0.11 (1)

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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