Introduction to Positron Emission Tomography (PET)!

Christine DeLorenzo!January 22, 2013!

In Vitro Measurements

From: Underwood et al, International Journal of Neuropsychopharmacology, August 2011 Receptor autoradiograms for the 5-HT1A receptor ([3H]8-OH-DPAT), the 5-HT transporter ([3H]cyanoimipramine), and the 5-HT2A receptor ([3H]ketanserin), and low magnification (upper right) and high power (lower right inset) of Nissl staining of a coronal section of tissue containing BA 47.

Serotonin in Depression Controls Depressed Subjects

From: RV Parsey

Alzheimer’s Disease Controls Alzheimer’s Disease

From: RV Parsey

Positron Emission positron emitting atom

neighboring atom

positron annihilation

! #1 ! #2

180°

Adapted from: brainimaging.waisman.wisc.edu/~oakes/TRO_PET_basics.pdf

Positron Emission Tomography

Adapted from: brainimaging.waisman.wisc.edu/~oakes/TRO_PET_basics.pdf

PET Radioisotopes

DJ Schlyer: PET Tracers and Radiochemistry, 2004

PET Tracers http://www.bic.mni.mcgill.ca/Facilities/PETTracers 11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime) Highly selective antagonist tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5) 11C-DTBZ (dihydrotetrabenazine) High affinity ligand of the vesicular monoamine transporter (VMAT2) 11C-PIB ( N-methyl-[11C]2-(4!-methylaminophenyl)"6-hydroxybenzothiazole) #Amyloid binding agent for imaging amyloid plaques 11C-Raclopride Dopamine D2 receptor antagonist 11C-SCH 23390 Dopamine D1 receptor antagonist 18F-fallypride’ Dopamine D2 receptor antagonist with high affinity, allowing cortical D2r visualisation 11C-PK 11195 Ligand of the mitochondrial Translocator Protein (TSPO; formerly designated as the peripheral benzodiazepine receptor), found in activated microglia (inflammation marker) 18F-PBR ([18F]Imidazo[1,2-a]pyridine) Also a ligand of the mitochondrial Translocator Protein (TSPO; formerly designated as the peripheral benzodiazepine receptor), found in activated microglia (inflammation marker). 18 F-MPPF Ligand of the serotonin receptor 5-HT1A; agonist 18F-Altanserin’ Ligand of the serotonin receptor 5-HT2A; agonist 18F-FDG’ (2-deoxy-2-[18F]fluoro-D-g1ucose) Glucose analog 18F-Flumazenil Ligand of the benzodiazepine receptor (cBZR) found on gamma-aminobutyric acid (GABA-A) receptors 18F-SFB (N-succinimidyl 4-[18F]fluorobenzoate) Can be used for labelling a variety of peptides and proteins with wide-ranging targets specificity 15O water [15O]water is used for measuring regional cerebral blood flow

Two Types of PET Applications

•  Clinical – Often Non quantitative

•  Research – Quantitative

Clinical - FDG In a retrospective study, F-18-fluorodeoxyglucose (FDG)- PET images of the brain predicted histological grade and survival in patients with gliomas. At this time, FDG-PET appears to be better than pathological grading for this purpose, Vasantha Padma, MD, of the Wallace-Kettering Neurosciences Institute, Kettering, Ohio, said at the 49th Annual Meeting of the Society of Nuclear Medicine (abstract 400).

Results showed that 94% of the patients with low FDG uptake (0-1 on the scale) lived for more than 1 year, and 19% survived for more than 5 years. Of these patients, 86% had low-grade gliomas (grade I-II). In contrast, only 29% of the patients with high FDG uptake (scores of 2-3) lived for more than 1 year, and none survived for more than 5 years. Of these high-uptake patients, 94% had high-grade gliomas (grade III-IV).

From: http://www.cancernetwork.com/news/display/article/10165/82408

Research = Quantitative

From: DeLorenzo et al, JCBFM, 2011

PET Overview Raw MRI

Segmentation

PET Overview Raw MRI

Segmentation

Parcellation

PET Overview Raw MRI Raw PET

Segmentation Motion Correction

Parcellation

PET is 4D

0.5 0.8 1.5 2.5 3.5 5.0

7.0 9.0 12.5 17.5 25.0 35.0

45.0 55.0 65.0 75.0 85.0 95.0

Register All to Frame 8

PET Overview Raw MRI Raw PET

Segmentation Motion Correction

Coregistration Parcellation

Tracer-Specific Coregistrations

NHPE2I001 dopamine transporters

NHWY225 serotonin receptors

NHDASB169 serotonin transporters

For WAY: No cerebellar binding Must exclude cerebellum from matching

For PE2I: High binding only in caudate/putamen/ventral striatum

PET Overview Raw MRI Raw PET

Segmentation

Time Activity Curves

Motion Correction

Coregistration Parcellation

PET is 4D

Time

Act

ivity

0.5 0.8 1.5 2.5 3.5 5.0

7.0 9.0 12.5 17.5 25.0 35.0

45.0 55.0 65.0 75.0 85.0 95.0

Modeling the TAC

Time activity curve

Plasma

Brain

K1 k2

Innis et al (2007) JCBFM 27:1533-1539

•  All measures are concentrations

•  BPF - closest measure to in vitro estimates! –  BPF = Bavail/KD, –  Bavail is the density of available receptors –  KD is the equilibrium dissociation constant –  fp is free fraction –  VND is the nondisplaceable volume of distribution

Binding Estimates

Innis et al (2007) JCBFM 27:1533-1539

Serotonin in Depression Controls Depressed Subjects

From: RV Parsey

Serotonin in Depression

0

10

20

30

40

50

60

70

80

90

100

RN AMY HIP PHG TEM ACN CIN DLPFC MPFC VPFC INS OCC PAR

Bin

din

g P

ote

nti

al

( BPF

, m

L/cm

3)

Controls 1 (n=42)

Controls 2 (n=9)

NRM 1 (n=8)

NRM 2 (n=22)

NRM 3 (n=15)

From: RV Parsey

Dopamine (D2) in Addiction

Volkow et al, Molecular Psychiatry, 2004

Dopamine Transporter (ADHD)

Volkow et al, NeuroImage, 2007

O-15 Water (Blood Flow)

Xu et al, NMR in Biomedicine, 2008

!"#$%&'#$(#)*$+*,+-./"0*$12+3*&#.1$4+

546"*$%+,*"+7484"4+9#":1$%*$’%+31%4#%4++

;<#$=4+1$+>?@A@'6*"*B*&#+C&(#:4+1$+(<4+D"#1$%+*,+9#)4$(%+E1(<+9#":1$%*$’%+31%4#%4+#F4"+!"#$%&'#$(#)*$G+#%+7<*E$+1$+@'6*"*B*&#+9-!+72#$%H++

;H+IH+@"44B+!"#$%&#5+-$='+J+K4B+LMM+NOPP>Q+R>PAR>S+

Receptor Occupancy

Receptor Occupancy

Adapted from: http://bensonintrobiology.concordcarlisle.wikispaces.net/serotonin

dopamine

dopamine receptor tracer

Receptor Occupancy

Adapted from: http://bensonintrobiology.concordcarlisle.wikispaces.net/serotonin

dopamine

dopamine receptor

Receptor Occupancy •  Dopamine antagonist PET tracers

– monitor dopamine transmission in disorders such as schizophrenia and substance abuse

•  Drug Development

Guo N et al (2009) Neuropsychopharmacology 35(3)806-817

Caffeine (adenosine receptors)

Elmenhorst, JNM, 2012

Drug Development

The End