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
Linear accelerator
High energy allows separation of rare 14C from other isotopes
99.8%
1.1%
10-11%
12C
Analysing magnet
13C
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 B + β+ + v + energy (97keV)
PET Camera β+ 
11C 
PET Camera 6

7. AMS & PET AMS PET Combination IN THE SAME SUBJECTS 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) 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
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. Microdose + therapeutic dose
Plasma Data Summary
R-verapamil
Microdose + therapeutic dose
Microdose

13. Microdose + therapeuticdose
Plasma PK Data Summary
Parameter
Enantiomer
Microdose
Microdose + therapeuticdose
t1/2 (h) R
6.3 ±1.9
6.9 ±1.6 S
7.2 ±2.5
7.1 ±2.2
Cmax (pg/mL)
210.1 ±79.2
243.8 ±77.7
96.3 ±28.6
103.5 ±33.6
AUC(0-24) (hpg/mL)
579.8 ±107.4
794.0 ±265.1
272.6 ±70.7
313.8 ±59.7
AUC(0-inf) (hpg/mL)
624.5 ±131.6
843.2 ±281.1
308.6 ±79.3
343.3 ±58.9
CL (L/h)
61.0 ±12.6
46.9 ±10.9
89.7 ±24.2
78.2 ±14.7
V (L)
528.2 ±95.1
465.7 ±133.0
912.9 ±341.9
789.0 ±272.8
Vss (L)
397.9 ±89.8
319.9 ±68.7
682.0 ±167.0
600.6 ±187.6

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

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

16. PET Data Summary Parameter Microdose Microdose + therapeutic dose
K1 (mLmL-1min-1)
0.030±0.003 (10)
0.031±0.005 (8)
k2 (min-1)
0.099±0.006 (49)
0.095±0.008 (40)
k3 (min-1)
k4 (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