1. ANALYSIS OF PET STUDIES Turku PET Centre 2001-05-07 V Oikonen PET Raw Data (sinogram) Results Parametric Sinogram PET Image Parametric Image Regional TACs + Blood Data Reconstruction Model CalculationsReconstruction Model Calculations Drawing Regions Drawing Regions SPM

2. BLOOD DATA Venous Bolus Infusion Arterial Time-Activity Curve (TAC) tt Mixing in Plasma Volume Exchange with Interstitial Volume Exchange with intracellular Volume Time Delay

3. BLOOD vs PLASMA Tracer Persists in Red Blood Cells (RBC) [ 15 O]O 2 [ 15 O]CO Blood Plasma c t Note that the metabolite of [ 15 O]O 2 is [ 15 O]H 2 O, which is in equilibrium between plasma and RBC C Blood = HCR*C RBC

4. BLOOD vs PLASMA Tracer Persists in Plasma [ 11 C]Palmitate [ 18 F]FTHA [Carbonyl- 11 C]WAY-100635 Blood Plasma c t C Blood = (1-HCR)*C Plasma Note that one of the labeled metabolites of palmitate is [ 11 C]CO 2, which penetrates RBC membrane

5. BLOOD vs PLASMA Tracer Penetrates RBC Membrane Instantly [ 15 O]H 2 O [ 11 C]FETNIM [ 18 F]CFT [ 11 C]HED [ 11 C]FLB-457 [ 11 C]MP4A Blood Plasma c t C Blood = HCR*C RBC + (1-HCR)*C Plasma Note that the concentration may be different in RBC and in plasma. Note that a labeled metabolite may not penetrate RBC membrane.

6. BLOOD vs PLASMA Tracer Penetrates RBC Membrane Slowly [ 18 F]FDOPA [ 11 C]Methionine [ 18 F]FDG Blood Plasma c t Note that the concentration may be different in RBC and in plasma. Note that a labeled metabolite may not penetrate RBC membrane. C Blood = HCR*C RBC + (1-HCR)*C Plasma

7. METABOLITES IN PLASMA

8. PET DATA ”input””output” Authentic tracer concentration available in arterial blood Concentration in tissue measured by PET scanner Perfusion Endothelial permeability Vascular volume fraction Transport across cell membranes Specific binding to receptors Non-specific binding Enzyme activity

9. MODEL CALCULATIONS ”black box” BLOOD or PLASMA TAC TISSUE TAC -sinogram or -image or -regional RESULTS (model parameters) MODEL

10. MODEL CALCULATIONS ”Garbage In-garbage Out” Paradigm PERFECT MODEL GARBAGE MODEL GARBAGE DATA PERFECT DATA GARBAGE RESULTS GARBAGE RESULTS

11. COMPARTMENTAL MODEL C P = concentration of tracer in plasma C F = free tracer in brain C B = receptor bound tracer C NS = non-specifically bound tracer K 1 -k 6 = rate constants; the fraction of tracer that is leaving compartment in time unit

12. DISTRIBUTION VOLUME Constant Infusion of Tracer after equilibrium is achieved Bolus Infusion of Tracer

13. DISTRIBUTION VOLUME Receptor Model Binding Potential: B’ max = density (concentration) of free receptors K d = dissociation rate constant

14. RECEPTOR DENSITY and affinity to the ligand

15. DISTRIBUTION VOLUME Distribution Volume Ratio DV in reference region: Reference region = (brain) region which has no receptors, i.e. region with no specific binding, i.e. region where k 3 =0 and B max =0, and thus BP=0 Distribution Volume Ratio:

16. LOGAN ANALYSIS Plasma Input Distribution volume = Slope of the Logan plot Distribution volume Ratio = Ratio of slopes of the ROI and reference region Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol 2000;27:661-670

17. LOGAN ANALYSIS Reference Region Input Distribution volume Ratio = Slope of the Logan plot calculated using reference region input Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol 2000;27:661-670 BP = DVR - 1

18. LOGAN ANALYSIS Summary For reversible binding Linearity of the plot must be checked Plasma/Reference region input Result: DV or DVR Easily applied to image or sinogram data

19. SIMPLIFIED REFERENCE TISSUE MODEL Only for tracers with simple kinetics No plasma samples nor metabolite analysis Result: BP and R 1 Easily applied to image data with RPM Could be applied to sinogram data Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. NeuroImage 1996;4:153-158

20. RATIO METHOD BP = (ROI - REF) / REF Region-of-interest (ROI) to reference region ratio correlates with density of available receptors

21. GJEDDE-PATLAK ANALYSIS ”Irreversible” uptake ARTERIAL PLASMA IRREVERSIBLE COMPARTMENT(S)

22. GJEDDE-PATLAK ANALYSIS Graphical Analysis Plot is linear after the tracer concentration in plasma and in reversible compartments are in equilibrium Slope of the linear phase of plot is the uptake (influx) rate constant K i Unit of K i is min -1, or (mL tissue/mL plasma)min -1 Patlak CS, Blasberg RG. Graphical evaluation of blood-to- brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 1985;5:584-590. Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol 2000;27:661-670

23. GJEDDE-PATLAK ANALYSIS Metabolic Rate of Glucose Glucose Glucose- 6- Phosphate Glucose K1K1 k3k3 k2k2 k4k4 [ 18 F]FDG [ 18 F]FDG - 6- Phosphate [ 18 F]FDG K* 1 k* 3 k* 2 k* 4 Lumped constant (LC) corrects for the different affinities of transporters and hexokinase to glucose and FDG Influx rate constant: Unit of MR glu :

24. GJEDDE-PATLAK ANALYSIS Summary For irreversible uptake Linearity of the plot must be checked Plasma/Reference region input Result: K i (influx rate constant) Easily applied to image or sinogram data

25. RETENTION INDEX ”one-sample Patlak plot” Requirements for data: -one late-time PET frame (static image), C T -TAC of authentic tracer from beginning, C P

26. PERFUSION Kety-Schmidt: change in tissue concentration is equal to the difference between arterial and venous concentrations (C A and C V ) multiplied by blood flow, f For [ 15 O]H 2 O:

27. PERFUSION Autoradiography Procedure: 1.Bolus [ 15 O]H 2 O infusion 2.Arterial blood sampling 3.Static Imaging (90 or 250 s) 4.Blood and PET TACs corrected for radioactive decay 5.Correction for time delay 6.Blood TAC corrected for dispersion 7.Calculation of look-up table using measured and corrected blood TAC 8.Image pixel values are replaced by flow values from the look-up table Look-up Table