2. Positron Emission Tomography for Antidepressant Binding Sites Paul Cumming, Dirk Bender, Albert Gjedde, Kathi Marthi, Svend Borup Jensen, and Donald Smith Aarhus PET Centre

3. Receptors and binding sites linked to antidepressant action: Serotonin transporters Noradrenaline transporters Dopamine transporters (monoamine oxidase) Adrenergic receptors Phosphodiesterase

4. An excellent ligand for detection of serotonin transporters in vitro

5. TotalNon-specific

8. [ 3 H]Paroxetine was used for autoradiographic studies ex vivo of SERT in rat brain Rats (n=24) were killed at times between two and 240 minutes after injection of [ 3 H]paroxetine (50 uCi, i.v.)

9. [ 3 H]paroxetine at 4 hours

13. Conclusion: [ 3 H]paroxetine binding has not reached equilibrium in rat brain at four hours

15. Positron Annihlation (UCLA-Crump Institute)

16. PET imaging (UCLA-Crump Institute)

19. PigVervet monkey 50 ml75 ml

20. Criteria for a ”good” PET tracer Rapid radiosynthesis with high specific activity Not metabolized too quickly in plasma No centrally-acting plasma metabolites Not entirely bound to plasma proteins Permeable to the blood-brain barrier Equilibrium binding obtained in < 60 min. Displaceable from specific binding sites

21. A dynamic PET recording for a ”good tracer” with arterial sampling allows the mapping in brain of two parameters: The distribution volume (V d, ml g -1 ) relative to the arterial input The specific binding (pB, B max /K d ) relative to a non-binding region (cerebellum)

22. [ 11 C]citalopram has been tested as a PET ligand But failed because of rapid metabolism in plasma

23. [ 11 C]5-methylnitroquipazine

24. [ 11 C]nitroquipazine 750 MBq Summed image [ 15 O]-water Oct 4, 1995

27. baseline +paroxetine 0.5 -0.2 pB [ 11 C]nefopam (n=1) Feb 15, 1995

29. 0.4 -0.1 pB baseline+pargyline (two hours) [ 11 C]venlafaxine (n=1) May 3, 1995

31. 10 0 V d (ml g -1 ) [ 11 C]NS 4194 (n=3) baseline +citalopram

33. [ 11 C]NS 2495 (n=1) baseline+citalopram

35. baseline+citalopram 24 0 V d (ml g -1 ) 0 pB 0.9 [ 11 C]NS 6417 (n=1) Sept. 23, 2003

37. 9 0 V d (ml g -1 ) Baseline + Citalopram [ 11 C]DASB (n=3)

38. [ 11 C]DASB (n=3)

40. Classical antidepressants are noradrenaline uptake site inhibitors [ 11 C]MeNER has recently been developed for measuring these sites

41. Baseline (June 15, 2004) DMI blocking 9 ml g -1 V d Zhou multi-linear arterial input

42. Atypical antidepressants can bind to adrenergic receptors e.g. [ 11 C]mianserin

44. 15 0 V d (ml g -1 ) 0.75 0 pB [ 11 C]mianserin (n=1) May 23, 2000

45. 0.55 -0.2 pB [ 11 C]mianserin (n=1) SA1SA2 SA3SA4 Aug 22, 2000

48. [ 11 C]Mirtazapine and clonidine Total10 -10 M 10 -9 M 10 -8 M 10 -7 M 10 -6 M 10 -5 M Total 10 -10 M 10 -9 M 10 -8 M10 -7 M10 -6 M 10 -5 M

49. [ 11 C]Mirtazapine and clonidine

50. 2 0 pB baselineclonidine (0.3 mg/kg) clonidine (3 mg/kg) [ 11 C]mirtazapine

51. 2 0 pB baselineyohimbine (0.3 mg/kg) yohimbine (3 mg/kg) [ 11 C]mirtazapine

53. 16 0 V d (ml g -1 ) SA1SA2SA3 [ 11 C]rolipram (n=1) April 22/03