From Vision to Seeing: Tracing Erich's role in bringing positron emission tomography to BC and Canada.

Transcription

1 Canada s National Laboratory for Particle and Nuclear Physics Laboratoire national canadien pour la recherche en physique nucléaire et en physique des particules From Vision to Seeing: Tracing Erich's role in bringing positron emission tomography to BC and Canada. Thomas J. Ruth, PhD Senior Research Scientist, Emeritus TRIUMF/BC Cancer Agency Owned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council Canada Propriété d un consortium d universités canadiennes, géré en co-entreprise à partir d une contribution administrée par le Conseil national de recherches Canada 1

2 Brief History of PET 1950s Brownell & Sweet at Harvard 1950s/60s Hospital based cyclotorn production of H 2 15 O, Ter Pogossian, Wash. U. 1960s 11 C-chemistry, Wolf team at BNL 1960s 14 C-deoxyglucose, Sokoloff, NIH 1960s/70s Kuhl & Edwards, MkIV camera 1970s Phelps & Hoffmann, PET scanner, Wash. U. 1970s 18 F-fluorodeoxyglucose, Wolf, Fowler, Ido 1970s 1 st FDG scan, Reivich, Kuhl, PENN 1980 NIH funded 10 sites for NeuroPET 07 February 2015 Vogt Symposium 2

3 FDG scan on MkIV Kuhl,et al. Circa 1976, BNL/UPenn 07 February 2015 Vogt Symposium 3

4 UBC/TRIUMF Pat McGeer, Brian Pate, Bernie Reidel,Laurie Hall Building infrastructure: CP-42 Beam Line PETTVI Scanner Pipeline Erich Vogt 07 February 2015 Vogt Symposium 4

5 CP-42 Switching Magnet Funded by Vancouver Foundation, circa February 2015 Vogt Symposium 5

6 PETTVI Dedication February 2015 Vogt Symposium 6

7 PETTVI Scanner 07 February 2015 Vogt Symposium 7

8 PETTVI FDG image PETTVI: 4 detector rings separated by septa: 7 imaging planes In plane spatial resolution 9.2 cm Axial slice width: 11.6 mm Slice to slice distance: 14.4 mm Sensitivity < 0.5% It wobbled! 07 February 2015 Vogt Symposium 8

9 1 st and Last Scans on the PETTVI 07 February 2015 Vogt Symposium 9

10 Pipeline February 2015 Vogt Symposium 10

11 Pion TRIUMF 07 February 2015 Vogt Symposium 11

12 Parkinson s Disease A common neurodegenerative disorder Loss of dopamine neurons and nerve terminal causing loss of motor skills and speech Most common form of treatment is with L-dopa which is transformed into dopamine in the body Donald B Calne February 2015 Vogt Symposium 12

13 Preclinical Changes in Brain The first demonstration of subclinical dopaminergic impairment in people exposed to MPTP and in people carrying asymptomatic Parkinson-causing mutations. 07 February 2015 Vogt Symposium 13

14 MPTP In the 1980 s a designer drug with a small contaminant (MPTP) causing Parkinsonian symptoms was sold to several to drug users. 07 February 2015 Vogt Symposium 14

15 Ratio Normal Progression vs MPTP Exposure FD-PET Progression MPTP-exposed Controls p= Exposure st scan 2 nd scan February 2015 Vogt Symposium 15

16 Bob Miller (VPR, UBC) & Erich 07 February 2015 Vogt Symposium 16

17 ECAT 953B, Ruth, Miller, Gardner 07 February 2015 Vogt Symposium 17

18 Screenshot from ECAT 953B 07 February 2015 Vogt Symposium 18

19 18 F-Dopa Scans 07 February 2015 Vogt Symposium 19

20 07 February 2015 Vogt Symposium 20

21 Pre- transplant 1 yr after 2yrs after 4 donor- group 1-donor group placebo 07 February 2015 Vogt Symposium 21

22 ECAT 953B Scanner Paul Kinahan, UBC MSc student developed first 3D reconstruction code 07 February 2015 Vogt Symposium 22

23 Early 3D Scans ECAT February 2015 Vogt Symposium 23

24 TR19 (13) Magnet in factory 07 February 2015 Vogt Symposium 24

25 TR13 Dees 07 February 2015 Vogt Symposium 25

26 TR13 Cyclotron February 2015 Vogt Symposium 26

27 Radiopharmaceuticals Dopamine system 18 F-FDOPA 11 C-Methylphenidate 11 C-Dihydrotetrabenazine 11 C-Raclopride 07 February 2015 Vogt Symposium 27

28 Pacific Parkinson s Research Centre Goals: Determine the origins of PD Follow natural history of disease (Progression) Develop treatments Control complications of treatment A. Jon Stoessl - Director 07 February

29 18 F F-Dopa Tracers available with TR13 HO HO CH 2 C NH 2 H CO 2 H H HN 11 H 3 CO2 C C 6 H 5 H Methylphenidate DAT 11 CH3 O CH 3 O HO H H N Dihydrotetrabenazine O NH CH 2 H HO O 11 N CH 3 CH 2 CH 3 Cl Cl Raclopride 07 February 2015 Vogt Symposium 29

30 18 F-FD 11 C-MP 11 C-DTBZ 11 C-DTBZ 11 C-SCH VMAT2 Tyr DOPA DA 11 C-MP D1R D2/D3R 18 F-FD DAT 11 C-RACLOPRIDE 07 February 2015 Vogt Symposium 30

31 Asymmetric Parkinson s 18 F-Fluorodopa 11 C-Methylphenidate 11 C-Dihydrotetrabenazine F-Fluorodopa C-Methylphenidate C-Dihydrotetrabenazine 11 C-Dihydrotetrabenazine UBC/ TRIUMF PET 31

32 In vivo assessment of endogenous DA concentration DA DA Baseline Placebo Drug 11 C-Raclopride Endogenous DA competes with raclopride for the D2 receptor 0 Apomorphine-induced changes in raclopride binding Lower raclopride binding indicates higher dopamine concentration 32

33 Relationship between abnormal dopamine release and turnover and the subsequent development of complications of therapy 12 ESTIMATED LEVODOPA-INDUCED CHANGES IN SYNAPTIC DOPAMINE LEVELS Error Bars: ± 1 Standard Error(s) stable group fluctuator group hr 4hr 07 February 2015 Vogt Symposium 33

34 UBC/TRIUMF HRRT 07 February 2015 Vogt Symposium 34

35 High Resolution Research Tomograph 119,000 detector elements 4,000,000,000 lines of response > 1Gbyte of data per image frame 07 February 2015 Vogt Symposium 35

36 Crystal material: LSO/LYSO Crystal size 2.1 x 2.1 x 10 mm 3 07 February 2015 Vogt Symposium 36

37 FDG Images from the HRRT Axial Coronal Sagittal 07 February 2015 Vogt Symposium 37

38 Additional Questions for PET: New drugs for diabetes Spinal cord research Enzymology The mouse genome and knock in/out models Learning Dyskinesia Cancer research 07 February 2015 Vogt Symposium 38

39 micropet 32 detector modules (8x8) 1920 individual LSO elements ring diameter 17.2 cm 10 cm transaxial FOV 1.8 cm axial FOV volume resolution ~ 8 ml sensitivity: 200 cps/µci cost ~ $ 450K USD 10 April February 2015 Vogt Symposium 39

40 Validation of Tracers From the very beginning we validated the tracers we used We calibrated the scanners so that the regions of interest could be viewed as Bq/cm 3 With modelling the results could be interpreted with quantitative biological metrics 07 February 2015 Vogt Symposium 40

41 B (pmole/cc) VMAT in lesioned rat (comparing postmortem to Binding Potential (PET)) y = 129x R 2 = BP ND 07 February 2015 Vogt Symposium 41

42 11 C-DTBZ (rat) 11 C-raclopride in same rat. 07 February 2015 Vogt Symposium 42

43 What have we learned about Parkinson s Disease thus far? Preclinical changes in PET indices. Asymptomatic patients progress to disease. Early signs of compensation. Singular events can cause parkinsonism. Evidence of our Event hypothesis including progression. 07 February 2015 Vogt Symposium 43

44 Future of Research PET The tracers we presently use look at the system response to disease. What we need are tracers that look at the disease process itself. We need to get closer to the action! This will provide the basis for personalized medicine. 07 February 2015 Vogt Symposium 44

45 Collaborations Beyond UBC/TRIUMF PET: 18 F & FDG Supply 18 F - FDG mpet PET/CT 07 February 2015 Vogt Symposium 45

46 Acknowledgements Brian Pate Mike Adam Salma Jivan Ken Buckley Donald Calne Jon Stoessl Doris Doudet Many, many, many individuals required to enable a complex collaborative effort to be successful. 07 February 2015 Vogt Symposium 46

47 No matter how lost I was, Eric could be counted upon to set me straight! 07 February 2015 Vogt Symposium 47

48 Thank you! TRIUMF: Alberta British Columbia Calgary Carleton Guelph Manitoba McMaster McGill Montréal Northern British Columbia Queen s Regina Saint Mary s Simon Fraser Toronto Victoria Winnipeg York Merci! 07 February 2015 Vogt Symposium 48 48