PET i neuroscience – nu och i framtiden
Lars Farde Professor of Psychiatry, Karolinska Institutet Chief scientist, AstraZeneca TSC at KI
Nuklearmedi...
As of today: Major applications of molecular imaging in drug discovery and development.
Microdosing Drug occupancy at target of interest Biomarkers of pathophysiology
Microdosing - Brain exposure is critical for CNS-drugs • Low brain exposure - a significant reason for failure • Taylor E.M. (2002) Clin. Pharmacokinet. 41:81-92.
• Can be controled for by PET-microdosing • Injection IV of less than 1 microgram of labeled drug
• Primate study • CNS drug (mGluR5) • High brain exposure
• Primate study • Drug for a peripheral target (CB1) • Low brain exposure
Whole body PET-imaging 60 minutes after oral administration of an F-18 labeled drug.
High
Low
….two hours later
High
Low
Major applications of molecular imaging in drug discovery and development.
Microdosing Drug occupancy at target of interest Biomarkers of pathophysiology
11C]raclopride binding to D2-dopamine receptors
Control
Haloperidol, 4 mg/d
Raclopride is an original synthesis from former Astra in Södertälje
Farde et al, 1986
Suggested thresholds for antipsychotic effect and extrapyramidal side-effects (EPS)
D2 receptor occupancy (%)
100 80
EPS Antipsychotic effect
60 40 20 0 0
4 Dose; plasma concentration
8
Farde et al, Arch Gen Psych,1992, ”citation classique”
Drug target occupancy A measurable link between pharmacokinetics and pharmacodynamics
Simon Cervenka
18/09/2014
12
11C]raclopride binding to D2-dopamine receptors
Control
Haloperidol, 4 mg/d
Raclopride is an original synthesis from former Astra in Södertälje
Farde et al, 1986
The human genome About 20.500 protein-encoding genes Clamp et al, PNAS, 2007
A third of them are expressed in brain Accumulated portfolio of industry • Binds to 473 proteins (Drews et al, 1996)
Examples of original radioligand development at Karolinska Institutet 1982-2010 Monkeys • 160 radioligands examined after radiolabelling Man • 38 radioligands examined • 16-18 validated and suitable for applied studies world wide
The global toolbox targets about 50 brain proteins
Control Scanditronix PC384-15B 384 detectors 8-11 mm FWHM
Haloperidol, 4 mg/d
Farde et al, 1986
High Resolution Research Tomograph (2008) • Dedicated for neuroimaging • 120.000 detector elements • Fully operational Jan 2008 • Highest resolution in series (2.0 mm) • New reconstruction principle (PSF) provides improved resolution (1.5 mm)
Andrea Varrone
18 september 2014
17
High resolution imaging of [11C]flumazenil binding to benzodiazepine receptors
GABAA receptors in vivo and in post-mortem human brain [11C]flumazenil HR
[11C]flumazenil HRRT
[18F]flumazenil Autoradiography
Monoaminergic innervation of the human brain
• The shared organization may reflect phylogenesis • Implicated in fundamental functions, i.e adaptation to environment, emotions etc • Functions that are impaired in major psychiatric disorders
From Fuchs and Flügge, Dialogues Clin Neurosci. 2004;6:171-183.
