Positron Emission Tomography:
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1 Positron Emission Tomography: Tool to Study Pharmacokinetics and to Facilitate Drug Development Robert B. Innis, MD, PhD Molecular Imaging Branch National Institute Mental Health 1
2 Outline of Talk 1. PET has high sensitivity and specificity 2. PET used in therapeutic drug development 3. Pharmacokinetic modeling of plasma concentration and tissue uptake can measure receptor density 4. Study drug distribution: block distribution to periphery and increase distribution to brain 5. Study drug metabolism: inhibit defluorination 2
3 Imaging Receptors with PET 3
4 Positron Emission Tomography 4
5 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 5
6 Radioligand = Drug + Radioactivity 1. Drug administered at tracer doses a) No pharm effects b) Labels <1% receptors c) Labeled subset reflects entire population 2. Radioligand disposed like all drugs a) Metabolism & distribution 3. Radiation exposure 6
7 NIH Rodent PET Camera 18 F bone uptake rat Developed By: Mike Green & Jurgen Seidel 7
8 PET: Tool in Therapeutic Drug Development Determine dose and dosing interval Identify homogeneous group Biomarker for drug efficacy Monitor gene or stem cell therapy 8
9 Lazabemide blocks [ 11 C]deprenyl binding to monoamine-oxidase-b (MAO-B) Selegilene is more potent and longer acting than lazabemide 9
10 PET: Tool in Therapeutic Drug Development Determine dose and dosing interval Identify homogeneous group Biomarker for drug efficacy Monitor gene or stem cell therapy 10
11 Dopamine Transporter: Located on DA Terminals Removes DA from Synapse 11
12 SPECT Imaging of Dopamine Transporter in Caudate and Putamen of Human Brain 12
13 123 I-β-CIT Dopamine Transporter SPECT: Decreased in Parkinson s Disease Healthy Parkinson Stage 1 13
14 PET: Tool in Therapeutic Drug Development Determine dose and dosing interval Identify homogeneous group Biomarker for drug efficacy Monitor gene or stem cell therapy 14
15 Serial Dopamine Transporter Imaging in a Parkinson Patient Institute for Neurodegenerative Disorders 15
16 PET Imaging of Amyloid: Biomarker for Alzheimer s Disease 16
17 PET: Tool in Therapeutic Drug Development Determine dose and dosing interval Identify homogeneous group Biomarker for drug efficacy Monitor gene or stem cell therapy 17
18 Gene Therapy Using Viral Vectors Viral vectors deliver gene that synthesizes dopamine (DA) Infuse virus into striatum (target cells) Target cells express the DA gene 18
19 PET Dopamine Imaging in Hemi-Parkinson Monkey: Monitors gene for DA synthesis in right striatum pre post Control Gene: Lac-Z pre post DA Synthesis Gene: AADC 19
20 PET Imaging to Monitor Embryonic Stem Cell Treatment of Parkinson Disease in Rats Normal Unilateral Lesion Embryonic Stem Cells PET & MRI 20
21 Outline of Talk 1. PET has high sensitivity and specificity 2. PET used in therapeutic drug development 3. Pharmacokinetic modeling: plasma concentration and tissue uptake 4. Study drug distribution: peripheral benzodiazepine receptor 5. Study drug metabolism: inhibit defluorination 21
22 Brain Drug Brain Uptake of [ 18 F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy AUC=32 Time AUC=16 Time 22
23 Brain Drug Brain Uptake of [ 18 F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy AUC=32 AUC=16 Time Time Patient Healthy Inject Activity 20 mci 10 mci 23
24 Brain Drug Brain Uptake of [ 18 F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy AUC=32 AUC=16 Time Time Patient Healthy Inject Activity 20 mci 20 mci 24
25 Brain Drug Brain Uptake of [ 18 F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy AUC=32 AUC=16 Time Time Patient Healthy Inject Activity 20 mci 20 mci Weight 50 kg 100 kg 25
26 Brain Drug Brain Uptake of [ 18 F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy AUC=32 AUC=16 Time Time Patient Healthy Inject Activity 20 mci 20 mci Weight 100 kg 100 kg 26
27 Brain Drug Brain Uptake of [ 18 F]Fluoxetine: Measures Density of Serotonin Transporters Patient Healthy AUC=32 Time AUC=16 Time Patient Healthy Inject Activity 20 mci 20 mci Weight 100 kg 100 kg Liver disease Yes No 27
28 Brain Drug Plasma Drug Binding Potential (BP): Receptor Density * Affinity BP equals uptake in brain relative to how much drug is delivered via arterial plasma. AUC=16 BP = Area Brain Curve Area Plasma Curve BP = 16 2 = 8 AUC=2 Time 28
29 Brain Drug Plasma Drug Binding Potential: Independent of Injected Dose* Double Plasma Input =>Double Brain Response *If ligand does not saturate receptors - i.e., if tracer doses used AUC=32 BP 1st Time = 16 2 = 8 AUC=16 BP 2nd Time = 32 4 = 8 AUC=4 AUC=2 Time 29
30 BP can be calculated from the Area Under Curve (math integral) as well as rate constants (math differential). From curves of plasma and brain radioactivity over time, estimate rate constants of entry and removal to/from tissue. K 1 Plasma Brain k 2 BP K k
31 Tissue uptake is proportional to density of receptors and the affinity of the drug Binding Potential BP B K max D B max 1 K D B max affinity B K D 1 K max D receptor density dissociation binding constant binding affinity drug 31
32 SUMMARY PET KINETICS Organ uptake is proportional to receptor density and affinity of drug Binding Potential (BP) = density X affinity Drug Exposure to tissue is AUC of: plasma concentration vs. time Response (uptake) of tissue is AUC of: tissue concentration vs. time Response BP Exposure AUC AUC tissue plasma BP also equals ratio of rate constants of entry and removal to/from tissue K BP k
33 Major Point of PET Pharmacokinetics (in words) Plasma pharmacokinetics provides a limited view of what s happening to drug in plasma. PET provides a limited view of what s happening to drug in tissue. Concurrent measurement of drug in plasma and of drug in tissue allows quantitation of the target of drug action i.e., receptor. 33
34 Outline of Talk 1. PET has high sensitivity and specificity 2. PET used in therapeutic drug development 3. Pharmacokinetic modeling: plasma concentration and tissue uptake 4. Study drug distribution: peripheral benzodiazepine receptor 5. Study drug metabolism: inhibit defluorination 34
35 Translocator Protein (18 kda) a.k.a. peripheral benzodiazepine receptor 1. Mitochondrial protein highly expressed in macrophages and activated microglia 2. Exists in periphery and brain 3. Multiple potential functions: steroid synthesis, nucleotide transport 4. Distinct from typical benzodiazepine GABA A receptor in brain 5. Marker for cellular inflammation 35
36 Conc radioactivity in putamin (%SUV) Conc [ 11 C]PBR28 in plasma (%SUV) Receptor Blockade [ 11 C]PBR28 in Monkey Brain: more radioligand in plasma and brain BASELINE RECEPTORS BLOCKED 500 BP = 130 ml/cm BP = 1.7 ml/cm BRAIN PLASMA Time (min) Time (min) 36
37 Receptor blockade displaces from lung & kidney. Drives more to brain but doesn t bind there. Baseline Lungs Kidneys Heart Spleen Blocked PK mg/kg Brain 2 min 25 min 115 min 37
38 Incidental Stroke Original MRI (T1 ) PET 6 weeks after MRI Repeat MRI 8 weeks after PET Repeat MRI (FLAIR, edema) 38
39 TSPO identifies epileptogenic focus in 15 of 16 patients. Hirvonen et al., JNM,
40 Brain activity (%SUV) Brain activity (%SUV) Brain activity (%SUV) Brain activity (%SUV) Human with low uptake is similar to monkey with receptor blockade A) regular healthy subject B) odd healthy subject Time (min) Time (min) C) normal monkey D) pre-blocked monkey Time (min) Time (min) 40
41 No Binding to [ 11 C]PBR28 in Brain and Periphery Lungs Normal Binding Heart Kidneys Spleen 2 min 26 min 103 min No Binding (~10% subjects) 41
42 TSPO rs6971 polymorphism causes differential affinity for PBR28 Ala to Thr substitution Allelic frequency ~ 30%. Prevalence of homozygotes ~ 9% Codominant expression HAB - high affinity binding LAB - low affinity binding MAB - reduced binding (mixed affinity states) Owen, JCBFM
43 Brain Drug Brain Uptake of [ 18 F]Fluoxetine: Measures Density of Serotonin Transporters Patient Healthy AUC=32 Time AUC=16 Time Patient Healthy Inject Activity 20 mci 20 mci Weight 100 kg 100 kg Liver disease Yes No 43
44 Brain Drug Plasma Drug Binding Potential (BP): Receptor Density * Affinity AUC=16 BP = Area Brain Curve Area Plasma Curve BP = 16 2 = 8 AUC=2 Time 44
45 Experimental Design: Effect of TSPO genotype on PBR28 binding PET study 27 healthy volunteers In vitro binding: Leukocyte displacement assay In vivo binding: [ 11 C]PBR28 PET imaging Post-mortem study 47 healthy controls, 45 schizophrenia patients Specific [ 3 H]PBR28 binding in prefrontal cortex Comparison with and without genotype correction Kreisl, JCBFM
46 % [ 3 H] PK11195 specifically bound % [ 3 H] PK11195 specifically bound PET Study: Both TSPO genotype and leukocyte binding assay determine affinity status MAB HAB MAB LAB HAB log [PBR28 (M)] Kreisl, JCBFM % agreement between binding assay results and genotype One-site fit = HAB Two-site fit = MAB Owen, JCBFM
47 [ 11 C]PBR28 uptake (V T ) PET Study: [ 11 C]PBR28 binding is 1.4-fold higher in high affinity binders than mixed affinity binders HH HL Mean HAB = 4.5 ml cm -3 Mean MAB = 3.2 ml cm -3 Expect less than 2-fold difference because [ 11 C]PBR28 uptake represents specific and nonspecific binding 47
48 Conc radioactivity (%SUV) Conc [ 11 C]PBR28 (%SUV) PET Study: Greater brain uptake in HH subjects with similar plasma concentration as HL subjects HAB MAB Time after injection (min) Time after injection (min) Time after injection (min) 48
49 [ 3 H ] b i n R.B. Innis: Molecualr Imaging Nov. 16, 2001 Post-mortem study: High and mixed affinity binders also seen in schizophrenia patients SZ HC SZ HC SZ HC H A B M A B L A B Kreisl, JCBFM,
50 [ 3 H]PBR28 specific binding (fmol/mg) Post-mortem study: Correcting for TSPO genotype increases ability to detect difference in schizophrenia and controls SZ HC Without genotype as covariate p = With genotype as covariate p =
51 Summary PBR28 PET study: Leukocyte binding assay predicts TSPO genotype TSPO genotype influences [ 11 C]PBR28 total binding PBR28 Post-mortem study: TSPO genotype influences specific binding Genotype correction increases ability to measure difference in schizophrenia and controls Correcting for TSPO genotype expected to improve clinical use of [ 11 C]PBR28 51
52 TSPO imaging in Alzheimer s disease: William Kreisl, MD (Brain, 2013) Neuroinflammation a proposed contributor to Alzheimer s disease pathology Unclear if early or late phenomenon AD MCI Healthy Number (n) Age 63 ± 9 73 ± ± 6 MMSE 20 ± 4 28 ± 2 30 ± 0.4 Amyloid Positive Positive Negative 52
53 Results: [ 11 C]PBR28 uptake increased in Alzheimer s disease but not mild cognitive impairment AD MCI HC V T /f P
54 Conc Radioactivity (SUV) Conc Radioactivity (SUV) [ 11 C]PBR28 uptake increased in Alzheimer s disease in target but not background regions 4 3 Inferior parietal lobule AD 4 3 Cerebellum Control Time (min) Time (min) 54
55 [ 11 C]PBR28 binding (V T /f P ) [ 11 C]PBR28 binding (V T /f P ) R.B. Innis: Molecualr Imaging Nov. 16, 2001 [ 11 C]PBR28 binding greater in Alzheimer s in target regions after correcting for TSPO genotype Inf parietal cortex Cerebellum p = p = p = p = p = p = AD MCI HC 0 AD MCI HC n=19 n=10 n=13 55
56 [ 11 C]PBR28 binding (standardized) [ 11 C]PBR28 binding correlates with clinical severity across Alzheimer s disease spectrum r = p = Clinical Dementia Rating Scale Sum of Boxes score (standardized) 56
57 [ 11 C]PBR28 binding (V T /f P ) [ 11 C]PBR28 binding (standardized) Early onset AD patients have greater [ 11 C]PBR28 binding p = EOAD LOAD Age of onset (standardized) 57
58 Conclusions from Alzheimer s disease study Neuroinflammation occurs after conversion of MCI to AD and worsens with disease progression Neuroinflammation greater in early onset patients May explain precipitous course in early onset patients [ 11 C]PBR28 has promise for longitudinal study of AD Mark conversion from MCI to AD Assess response to treatments 58
59 Outline of Talk 1. PET has high sensitivity and specificity 2. PET used in therapeutic drug development 3. Pharmacokinetic modeling: plasma concentration and tissue uptake 4. Study drug distribution: peripheral benzodiazepine receptor 5. Study drug metabolism: inhibit defluorination 59
60 [ 18 F]FCWAY: Defluorination Bone uptake: human skull at 2 h 60
61 [ 18 F]FCWAY: Defluorination 18 F-fluoride ion accumulates in bone 61
62 Miconazole Inhibits Defluorination & Bone Uptake [ 18 F]Fluoride Skull Brain Skull Temp Ctx [ 18 F]FCWAY: Miconazole Baseline 15 mg/kg 30 mg/kg 60 mg/kg 62
63 Disulfiram: Decreases Skull Activity & Increases Brain Uptake Baseline Disulfiram Images at 2 h in same subject. Disulfiram 500 mg PO prior night 63
64 Mean %SUV Mean %SUV Disulfiram: Decreases skull uptake of fluoride & Increases brain uptake of [ 18 F]FCWAY Skull Temporal Cortex Baseline Disulfiram 200 Disulfiram 200 Baseline Time (min) Time (min) 64
65 Activity (Bq/mL) Activity (Bq/mL) Disulfiram: Decreases plasma fluoride & Increases plasma radiotracer [ 18 F]FCWAY [ 18 F]fluoride Baseline Disulfiram Time (min) [ 18 F]FCWAY (parent tracer) Disulfiram Baseline Time (min) 65
66 Summary 1. PET has high sensitivity and specificity 2. PET used in therapeutic drug development 3. Pharmacokinetic modeling of plasma concentration and tissue uptake can measure receptor density 4. Study drug distribution: block distribution to periphery and increase distribution to brain 5. Study drug metabolism: inhibit defluorination 66
67 Self-Assessment Quiz: True or False? Imaging with positron emission tomography (PET) involves the injection of a radioactively labeled drug that emits a particle called a positron. PET shows the location of radioactivity in a cross section (or tomograph) of the body. PET can be used to quantify the density of specific proteins in the body. Compartmental modeling of PET data typically uses measurements over time of 1) PET images of the target tissue and 2) concentrations of unchanged parent radioligand in plasma. 67
68 68 68
69 FDA Critical Path Initiative Approvals for new drugs declining R&D funding by industry and NIH is increasing Problem: tools are inadequate for efficient evaluation of new drugs in the critical path of development Still using old tools like liver enzymes and hematocrit to evaluate safety and efficacy Need new Product Development Toolkit 69
70 CRITICAL PATH to New Medical Products FDA, March 2004 There is currently an urgent need for additional public-private collaborative work on applying technologies such as new imaging technologies. Opportunity: Imaging technologies, such as molecular imaging tools in neuropsychiatric diseases or as measures of drug absorption and distribution, may provide powerful insights into the distribution, binding, and other biological effects of pharmaceuticals. 70
71 71
72 72
73 Brain Drug Plasma Drug Quantification of receptor density Distribution volume Uptake in brain relative to how much drug is delivered via arterial plasma AUC=16 VT = Area Brain Curve Area Plasma Curve VT = 16 2 = 8 AUC=2 Time after injection 73 73
74 Brain Drug Plasma Drug Quantification of receptor density Equilibrium method Distribution volume Concentration ratio of tissue to plasma under equilibrium Bolus injection Equilibrium method AUC=16 32 AUC=2 Time after injection Time after injection
75 Advantages of equilibrium method Determine VT directly from concentration ratio of tissue to plasma under equilibrium Less invasive Rapid equilibrium can be achieved with bolus and constant infusion 75
76 Rapid equilibrium with bolus plus constant infusion + From pharmacokinetic course 2009 by R.E. Carson 76
77 Radioactivity became stable in plasma and brain with bolus plus constant infusion Temporal cortex Thalamus Plasma parent 77
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