PET i neuroscience nu och i framtiden Lars Farde Professor of - PowerPoint PPT Presentation

PET i neuroscience – nu och i framtiden Lars Farde Professor of Psychiatry, Karolinska Institutet Chief scientist, AstraZeneca TSC at KI Nuklearmedicinens dag, Malmö, 2014-09-17

PET- publications in MedLine (2010) Oncology (total 2765 publ.) Neurology+psychiatry (total 3900 publ.) Number of publications Immunology (total 1347 publ.) Respiratory (total 724 publ.) Neurosurgery (total 998 publ.) Cardiology (total 576 publ.) Hematology (total 322 publ.)

MedLine search ”positron emission tomography” AND ”[organ]” Kidney 1.72% Brain 31.13% Lung 9.33% Cancer 37.10% March 2013

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 • Primate study • CNS drug (mGluR5) • Drug for a peripheral target (CB1) • High brain exposure • 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) 100 D 2 receptor occupancy (%) 80 EPS Antipsychotic effect 60 40 20 0 0 4 8 Dose; plasma concentration 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 •D2-dopamine • [11C]raclopride (1985) Monkeys • [11C]FLB457 (1997) •D1-dopamine • 160 radioligands examined • [11C]SCH23390 (1985) after radiolabelling • [11C]NNC112 (1995) •Dopamine transporter • [11C]PE2I (2004) Man •Serotonin transporter • [11C]MADAM (2003) • 38 radioligands examined •Serotonin 5HT2a • 16-18 validated and suitable • [11C]MDL100907 (1997) •Benzodiazepine for applied studies world wide • [11C]Flumazenil (1986) • [18F]Flumazenil (2006) •Norepinephrine transporter • [18F]FD2MeNER (2006) •Serotonin 5HT1b The global toolbox targets • [11C]AZ10419369 (2008) about 50 brain proteins •Amyloid Plaque • [11C]AZD2184 (2008) • [18F]AZD4694 (2009)

11C]raclopride binding to D2-dopamine receptors Control Haloperidol, 4 mg/d Scanditronix PC384-15B 384 detectors 8-11 mm FWHM 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

GABA A receptors in vivo and in post-mortem human brain [ 11 C]flumazenil [ 11 C]flumazenil [ 18 F]flumazenil HR HRRT 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.

PET imaging of brainstem nuclei: **: p <0.01 ***: p <0.001  High resolution PET imaging and WAPI enables images with enough resoltion and contrast for identification of the small brainstem nuclei.  The difference between HR and HRRT PET systems (~30-40%) is attributable to their disparate resolutions, providing support for that the estimated values are realistic.  The method allows for quantification of radioligand binding in small brainstem structures Martin Schain 18 September 2014 21

Major applications of molecular imaging in drug discovery and development.  Microdosing  Drug occupancy at target of interest  Biomarkers of pathophysiology

[ 18 F]FE-PE2I – a new selective radioligand for the dopamine transporter (DAT) Sasaki et al, J Nucl Med • Best in class of the more than 15 PET- and SPECT-ligands developed since 1989. • Together with HRRT: Detailed mapping of regional DAT binding in PD Varrone et al, 2011, Ito et al 2013

[ 18 F]FE-PE2I binding to DAT in PD BP ND Control H&Y 1 H&Y 1.5 H&Y 2 Parkinson

Regional Dopamine Transporter binding in PD A B ↓ 33% p <0.05 ↓ 70% p <0.05 BP ND ↓ 35% p <0.05 ↓ 28% n.s. Control PD H&Y 1 Figure . A) Representative [ 18 F]FE-PE2I parametric images of binding potential ( BP ND ) in one control subject and one PD patient. B) [ 18 F]FE-PE2I BP ND values in different brain regions in controls and PD patients. Manuscript in prep, Varrone et al

[ 11 C]PIB - the first ligand for imaging of amyloid deposits in Alzheimers disease [11C]PIB FDG Control AD Klunk et al, Annals of Neurol. 55, 2004 Samantha Budd, 2008-11-05

Using rational design to design a second generation amyloid PET radioligands 120 Testing of 1,000’s % Specific Binding 100 80 60 compounds 40 20 since 2003 0 -10 -9 -8 -7 -6 -5 -4 log AZAD [ 18 F]AZD4694 [ 18 F]AZD4694 6 6 Radioactivity (% ID) Radioactivity (% ID) 5 5 4 4 3 3 AZD2184 2 2 1 1 0 0 0 0 25 25 50 50 75 75 100 100 125 125 Time (min) Time (min) 11 C- amyloid PET ligand AZD4694 18 F- amyloid PET ligand 18/09/2014 27 LF

[ 18 F]AZD4694 showing amyloid deposits in Alzheimers Disease

Species differences  Rule rather than exception ! • regional expression • regional density Simon Cervenka 18/09/2014 29

Combined whole-body CT-PET-MR examination in vivo in mice using the nanoScan system (2012) CT CT-PET CT-PET-MR • Morphology with • Morphology with • Morphology with high resolution high resolution high resolution • Function with high sensitivity • Added soft tissue contrast • Function with high sensitivity PET: 10MBq 18 FDG, Resolution ~ 0.7 mm

Translational molecular imaging Molecular imaging Post mortem In vivo Post mortem Rodents: Non-human Human brain studies primates subjects TG and WT Autoradiography, µPET PET PET immunohisto- chemistry, etc. microdosing, occupancy, Longitudinal studies on disease biomarkers *all examples show raclopride binding to D2-dopamine receptors

[11C]raclopride binding to D2- dopamine receptors in the rat brain Dorsal striatum MRI <0.1 µ g Accumbens 0.88 µ g 2.86 µ g Häggkvist et al, manus in prep.

”Neuroinflammation”

TSPO – marker for microglia (The peripheral benzodiazepine receptor) • The Translocator Protein (TSPO) serves as a marker for microglia (monocytes) • Functions: Cholesterol transport, immunomodulation, protein import, apoptosis, cellular respiration/oxidative stress TSPO localisation in mitochondria Autoradiography in control brain in vitro (3H-PK11195) Papadopoulos et al 2006 Doble et al 1987

Microglia has been implied in the pathogenesis of: Multiple sclerosis Alzheimer´s disease Parkinson´s disease Depression Schizophrenia Stroke Epilepsy Amyotrophic lateral sclerosis Corticobasal degeneration Huntington´s disease HIV dementia Hepatic encephalopathy Banati et al, 2002 Glioma

PET radioligands for TSPO - a marker for microglia Reference radioligand [ 11 C]PK11195 Ki = 4.5 nM, cLogP =5.3 Second generation radioligands [ 11 C]DAA1106 [ 18 F]FEDAA1106 [ 11 C]DPA713 [ 11 C]CLINME [ 11 C]PBR28 Ki = 0.9 nM, cLogP =3.0 36

[11C] PBR28 binding By courtesy of Bob Innis and Vic Pike, NIMH

High resolution imaging of [ 11 C]PBR28 binding to TSPO in brain • Control subject, summation images of radioactivity 9-90 minutes after i.v. bolus injection of 359 MBq [ 11 C]PBR28 • High binding in lymphoid tissue in the neck region • Lymphoid tissue is rich in macrophages 38

TSPO at baseline: effect of SNPs  large interindividual variability in binding affinity: a trimodal distribution of high-affinity binders (HABs), low- affinity binder (LAB), and mixed-affinity binders (MABs).  polymorphism (rs6971) located in exon 4 of the TSPO gene, results in a nonconservative amino-acid substitution from alanine to threonine (Ala147Thr) in the TSPO protein. predicts total distribution volume in human brains 39