Functional Imaging with Positron Emission Tomography. Jeih San Liow, PhD Molecular Imaging Branch National Institute Mental Health

Transcription

1 Functional Imaging with Positron Emission Tomography Jeih San Liow, PhD Molecular Imaging Branch National Institute Mental Health

2 Outlines What is positron emission tomography (PET) Applications Imaging glucose metabolism Imaging transporter function at the blood brain barrier Imaging neuroimflammation Other targets

3 What is PET? Positron Emission Tomography Produce positron emitted radioactive isotopes Incorporate isotopes into compounds through chemical synthesis Inject compound into human body and image functionality

4 Positron Emission Tomography

5 Coincidence Imaging

6 Cyclotron

7 Common PET Isotopes Half Life (Min) Compounds 15 O 2 Water 13 N 10 NH3 11 C 20 CO, CO 2, Acetate 18 F 110 FDG, FDOPA

8 Radioligand = Drug + Radioactivity Drug administered at tracer doses No pharm effects Labels <1% receptors Labeled subset reflects entire population Radioligand disposed like all drugs Metabolism & distribution Radiation exposure

9 PET vs. MRI Spatial Resolution PET MRI 2 6 mm << 1 mm Sensitivity M 10-4 M Temporal Resolution minutes <1 sec Radionuclide ( 11 C): high sensitivity Ligand (raclopride): high selectivity Radioligand [ 11 C]raclopride: high sensitivity & selectivity

10

11 2D vs. 3D Acquisition

12 Random, scatter and true coincidence Scatter coincidence True coincidence Random coincidence

13 PET Image Formation Correction for error sources in the projection data Detector Normalization Random Correction Scatter Correction Attenuation Correction Decay correction Reconstruction Filter Backprojection (FBP) Order-subset Maximum Likelihood EM (OSEM)

14 Purpose of a CT scan in the PET/CT examination To perform attenuation correction To provide anatomical reference for localizing target of interest

15 Filtered Backprojection Reconstruction

16 Qunatification of PET images through compartmental models Free + nonspecific Specific

17 Depth of interaction (DOI) PET scanner with 2 layer of detector rings Single Layer Phoswich FF BF FB BB Front layer Back layer

18 Time of Flight (TOF) 1 light nano sec 30 cm

19 Siemens mct Biograph (PET/CT)

20 HRRT PET Scanner (High Resolution Research Tomograph) Gantry Opening 35 cm Image field of view (FOV) 31.2 cm (transverse); 25.2 cm (axial) Crystal LSO (10 mm) + LYSO (10 mm) Block 8 x 8 elements (each 2.1 x 2.1 mm) # of blocks in a bank 9 (transverse) x 13 (axial) # of banks 8 # of detectors per plane 1152 Axial > 25 cm Total # of detectors Total # of line of response (LOR) 4.48 x 10 9 # of 2D plane 207 Linear/Angular sampling (sinogram) Slice thickness Resolution 1.2 mm / 0.6 degree (256 x 288) 1.2 mm 2.5 mm (transverse); 3 mm (axial)

21 Motion Correction: HRRT Polaris infrared tracking system * No correction Motion corrected

22 MicroPET scanner for small animals Focus 220 (nonhuman primate) Focus 120 (rodent) Axial field of view 7.5 cm Resolution 1.6 mm FWHM

23 Wearable PET scanner (Craig Woody, BNL) For conscious rat brain imaging Resolution 2 mm FWHM

24 Imaging glucose metabolism

25 [ 18 F]Fluorodeoxyglucose (FDG) to measure glucose metabolism X Irreversible binding

26 Typical Whole Body PET Procedure [ 18 F]FDG Injection of 5-10 mci of FDG Scan begins minutes after injection 7 position emission scans, 5 minutes each Whole body CT scan prior to injection ( < 1 minute) for attenuation correction and anatomical reference

27 Courtesy of University of Pittsburgh Medical Center

28

29 Lung cancer: Attenuation correction increases the contrast of deep structure thus provides more accurate quantification No attenuation corr with attenuation corr

30 Esophageal cancer: comparison of two different image reconstruction algorithms FBP OSEM Coronal Axial

31 Hodgkin s Lymphoma: Before and after chemotherapy Pretreatment Post trteatment

32 PET/CT image fusion CT PET PET/CT

33

34 Cardiac PET: Hibernation

35 Imaging transporter function at the blood brain barrier

36 Transporters at the BBB control brain uptake 3 most common ABC transporters: ABCB1 P glycoprotein (P gp, 50%) ABCG2 Brest cancer resistant protein (BCRP, 30%) ABCC1 Multidrug resistant protein (MRP1, 20%) Influx P-gp ABCG2 MRP Active Efflux Drug uptake depends on BBB and affinity for transporters Clinical challenge to effective therapeutic interventions 98% of small molecule drugs do not pass through the BBB Plays a role in the pathophysiology of CNS diseases Pardridge, 2012, JCBFM, Loscher et al Nat Rev Neuro; Levin et al J. Med. Chem. 30 min after intravenous injection of radiolabeled histamine

37 P-glycoprotein removes lipophilic substrates directly from the plasma membrane substrate + OUTSIDE + P-gp MEMBRANE + + ATP ATP + INSIDE

38 [ 11 C]dLop: brain uptake > 4 fold higher in P gp KO than in wild type mice MRI WT P gp KO Conc Activity (%SUV) P-gp KO WT Time (min) Loperamide is an opioid agonist which does not cross the BBB Desmethyl loperamide (dlop) is a metabolite of loperamide which also acts as a substrate of P gp

39 P gp blockade increases uptake of [ 11 C]dLop in monkey brain but not in pituitary Baseline P gp blockade (with DCPQ) Brain Pituitary gland

40 Brain uptake of [ 11 C]dLop increases after P-gp inhibition and is trapped Naloxone DCPQ Baseline DCPQ 16 mg/kg (P gp inhibitor) Naloxone 5 mg/kg (opioid antagonist)

41 Minimal brain uptake of [ 11 C]dLop in healthy human brain PET Fused MRI 20 Pitiutary gland Conc radioactivity (%SUV) Time after injection (min)

42 [ 11 C]dLop: 0-10 min no entry to brain

43 Tariquidar a potent P gp inhibitor at 6 mg/kg increases [ 11 C]dLop uptake by 250% Baseline %SUV 400 B Tariquidar 6 mg/kg 0

44 Brain uptake of [ 11 C]dLop increases dose dependently after inhibition of P gp Brain uptake (%SUV min) Tariquidar dose (mg kg -1 )

45 [ 18 F]FCWAY: Brain uptake increases after P glycoprotein inhibition in human Conc radioactivity (SUV) Hippocampuc (TQD) Hippocampus (BL) Striatum (TQD) Striatum (BL) V T baseline tariquidar Time (min) 0 HP Insula Cin ST AMY CE Paired t test, one tailed, p < 0.02, n=8 FCWAY is a serotonin 1A receptor (5HT 1A ) antagonist a weak substrate of P gp at the blood brain barrier

46 Imaging neuroinflammation

47 Translocator Protein (TSPO) aka Peripheral Benzodiazepine Receptor 1. Mitochondrial protein transports cholesterol to enzyme that synthesizes pregnenolone 2. Highly expressed in macrophages, activated microglia, & reactive astrocytes 3. Marker for activation of the immune system in brain: neuroinflammation

48

49 Imaging Brain Infarction in Rats using [ 11 C]PBR28 Middle cerebral artery occlusion (MCAO) In vitro [ 3 H]PK11195 autoradiography Cresyl violet staining [ 11 C]PBR28 PET Peri-ischemic core Contralateral Ischemic core

50 Incidental Stroke Original MRI (T1 ) PET 6 weeks after MRI Repeat MRI 8 weeks after PET Repeat MRI (FLAIR, edema)

51 TSPO identifies gliosis in epileptogenic focus

52 Genetical variability of binding affinity to [ 11 C]PBR28 in Brain and Periphery Lungs Normal Binding Heart Kidneys Spleen 2 min 26 min 103 min No Binding (~10% subjects)

53 TSPO increased in Alzheimer s disease (AD) but not mild cognitive impairment (MCI) Control vs MCI vs mild AD Healthy volunteer Mild cognitive impairment Alzheimer s disease MMSE = 30 MMSE = 27 MMSE = 23 53

54 [ 11 C]PBR28 binding greater in Alzheimer s in target regions after correcting for TSPO genotype Inf parietal cortex Cerebellum p = p = p = p = [ 11 C]PBR28 binding (V T /f P ) p = AD MCI HC n=19 n=10 n=13 [ 11 C]PBR28 binding (V T /f P ) p = AD MCI HC

55 [ 11 C]PBR28 binding correlates with clinical severity across Alzheimer s disease spectrum [ 11 C]PBR28 binding (standardized) r= p = Clinical Dementia Rating Scale Sum of Boxes score (standardized)

56 Early onset AD patients have greater [ 11 C]PBR28 binding p = EOAD LOAD [ 11 C]PBR28 binding (VT/fP) [ 11 C]PBR28 binding (standardized) Age of onset (standardized)

57 [ 11 C]PBR: A rat inflammation model after injecting LPS into the right striatum Day Activity (Bq/mL) Ipsi Contra Time (min) LPS: Lipopolysaccharide

58 PET Imaging of other targets

59 PET Imaging to Monitor Embryonic Stem Cell Treatment of Parkinson Disease in Rats ([ 18 F]FECNT: a dopamine transporter probe) Normal Unilateral Lesion Embryonic Stem Cells PET & MRI

60 [ 18 F]FCWAY: Disulfiram decreases Skull Activity & Increases Brain Uptake Baseline Disulfiram Images at 2 h in same subject. Disulfiram 500 mg PO prior night

61 [ 11 C]PIB & [ 18 F]FDG PET scans in Alzheimer s disease PIB: Pittsburgh compound B, a biomarker for amyloid plaque commonly present in AD brain

62 [ 18 F]FDOPA uptake in the striatum Normal Vs. Parkinsonian Normal Parkinsonian

63 [ 18 F]FIMX: high binding to metabotropic glutamate type 1 receptor (mglur1) in the cerebellum and blocked by mglur1 antagonist Nonhuman primate SUV baseline SUV blocked Cerebellum Thalamus Caudate Caudate Thalamus Cerebellum min Human min

64 Oxytocin: The love receptor [ 11 C]Oxytocin scan in monkey show small specific binding Baseline Insel & Young, Nature Neuroscience, Feb Prairie vole: monogamous Montane vole: polygamous Blocked

65 [ 18 F]Fluoride: Bone scan of a rat (NIH ATLAS small animal PET scanner)

66 PET: Tool in Therapeutic Drug Development Determine dose and dosing interval Identify homogeneous group Biomarker for drug efficacy Monitor gene or stem cell therapy

67 Thank you