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A New Liver Imaging Agent David R. Vera, PhD Department of Radiology

Explore redesigning an agent to measure effective plasma flow in liver imaging without altering its chemical structure. Understand the molecular target ASGP-R, its specific properties, and applications. Study kinetic parameters and design considerations for optimal affinity. Investigate NAFLD, NASH, and liver diseases. Design an experimental model to distinguish early fibrosis using Ga-68 GSA functional imaging. Conclusions on measuring effective plasma flow and identifying fibrosis scores in liver disease research.

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A New Liver Imaging Agent David R. Vera, PhD Department of Radiology

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  1. 0 A New Liver Imaging Agent David R. Vera, PhD Department of Radiology University of California, San Diego

  2. 0 New Measurements from an Old Liver Imaging Agent David R. Vera, PhD Department of Radiology University of California, San Diego

  3. 0 Redesign an Agent to Measure Effective Plasma Flow It was Initially Designed to Measure Tissue Function (receptor concentration) We Will not Alter the Chemical Structure

  4. TcNGA: UC Davis mid-1980sTcGSA: Nihon Mediphysics 1992 Stadalnik et al J Nucl Med 1985; 26: 1233

  5. 0 The Molecular Target:The Asialoglycoprotein Receptor ASGP-R • Specific for galactose-terminated macromolecules • Hepatocytes only • High capacity • No pharmacology

  6. [99mTc]-Galactosyl-NeoglycoalbuminTcNGA Receptor Substrate: Galactose Backbone: Human Serum Albumin Reporter: Technetium-99m Vera et al Radiology 1984; 151: 191

  7. Galactosyl-Neoglycoalbumin: GSA Receptor Substrate: galactose Backbone: HSA Chelator: DTPA Radioactive Atom: Tc-99m

  8. 0 Introduction[68Ga]GSA Uptake is Determined by Multiple Factors: effective hepatic plasma flow, Fhepatic plasma volume (reaction volume), Vhreceptor affinity, kbreceptor concentration, [R]o

  9. [99mTc]Galactosyl-Neoglycoalbumin Rabbit, iv injection (~ 500 uCi) Dynamic imaging (0 – 20 mins, 5 sec/frame), liver Planar imaging Radiology 1984; 151: 191-196

  10. Receptor-Binding RadiotracersBimolecular Reaction • [R] Receptor Concentration • kbForward Binding Rate Constant • k-bReverse Binding Rate Constant

  11. Kinetic ParametersBimolecular Reaction Rate uptake rate = kb[L][R] kb Forward Binding Rate Constant [R] Receptor Concentration [L] Ligand Concentration

  12. Forward-Binding Rate ConstantDefinition

  13. Binding assay Slope=KD

  14. Revbinding assay

  15. Reverse-Binding Rate Constant Definition

  16. Control of affinity Vera et al J Nucl Med 1984; 25: 770

  17. Design Decisions What is the optimal affinity? Low number of galactose units per HSA? High number of galactose units per HSA? What amount of NGA should we inject? Should we use a “tracer dose” (Lo << Ro)? Should Lo approximate Ro?

  18. Kinetic Model: TcNGA Vera et al J Nucl Med 1991; 31: 1169

  19. Vera et al IEEE BME 1983; 13: 311

  20. Vera et al IEEE BME 1983; 13: 311

  21. Parameter IdentifiabilityConclusions: Moderate affinity Avoid high tissue extraction Inject an adequate amount of ligand Lo should approximate Ro use 26 pmol/g of body weight

  22. Generate Time-Activity Curves Y1 Data Set Heart TAC Y2 Data Set Liver TAC Last of 120 frames from zero to 30 minutes

  23. Curfit healthy

  24. Curfit healthy

  25. Curfit cirrhosis

  26. Cirrhotic Patient [R]o = 0.270 kb = 2.94 Ve = 2.44 Vh = 0.267 F = 0.454 Healthy Subject 0.914 mM 2.23 mM-1 min-1 1.99 L 0.274 L 0.685 L min-1 patcfr

  27. Healthy Subject [R]o = 0.914 ± 0.099 mM kb = 2.23 ± 0.73 mM-1 min-1 Ve = 1.99 ± 0.02 L Vh = 0.274 ± 0.001 L F = 0.685 ± 0.384 L min-1 norcrf

  28. Cirrhotic Patient [R]o = 0.270 ± 0.018 mM kb = 2.94 ± 1.38 mM-1 min-1 Ve = 2.44 ± 0.09 L Vh = 0.267 ± 0.005 L F = 0.454 ± 0.858 L min-1 patcfr

  29. 0 Pimstone et al. Hepatology 1994

  30. Vera et al J Nucl Med 1997; 37: 160

  31. 0 NonAlcoholic Fatty Liver Disease (NAFLD) Spectrum of disease NonAlcoholicSteatohepatitis (NASH) Early Fibrosis Cirrhosis Inflammation, Late Fibrosis + Steatosis NAFLDSteatosis small percent HepatomaPrimary Liver Cancer

  32. 0 Nonalcoholic SteatohepatitisScope of the Problem in U.S. } • Prevalence NAFLD: ~ 20-23%% • Prevalence of NASH: 2-3% • NASH:- severe fibrosis: 15-50% - cirrhosis: 7-16%- rate of liver-specific mortality in NASH cirrhotics: ~ 10% per decade - risk for hepatoma The most common chronic liver disease

  33. 0 NAFLD Prevalence • Obesen Patients-NAFLD: 60-90%-NASH: 20-25%-Cirrhosis:2-3% • Diabetic Patients:-NAFLD: ~ 50% -NASH: 25% -Cirrhosis: 8% • Obese + Diabetic:-NAFLD: 100%-NASH: 50%-Cirrhosis: ~20%

  34. Design DecisionsMeasure Effective Plasma Flow What is the optimal affinity? Low number of galactose units per HSA? High number of galactose units per HSA? What amount of NGA should we inject? Should we use a “tracer dose” (Lo << Ro)? Should Lo approximate Ro?

  35. Kinetic Model: TcNGA Vera et al J Nucl Med 1991; 31: 1169

  36. Vera et al IEEE BME 1983; 13: 311

  37. Parameter IdentifiabilityTo Measure Effective Plasma FlowConclusions: Moderate or High affinity Inject an adequate amount of ligand Lo << Ro use 1.5 pmol/g of body weight

  38. 0 68Ga-GSA can distinguish early Fibrosis?Experimental Design Use two models of rat liver Disease Fibrosis: DEN treatment (4, 8, 10, or 12 weeks) Fatty Liver: CDAA treatment (4, or 8 weeks) Use healthy rats Perform Ga-68-labeled GSA functional imaging (45 - 95 µCi, 1.5 pmol/g total body weight) Calculate T90 (time of liver to reach 90%) Section liver for histology Determine Fibrosis Score (F0 – F4) based on histology

  39. 0 Fibrosis Score F0 No Fibrosis F1 Mild Fibrosis (short septa extending in the perisinusoidal space in any zone) F2 Moderate Fibrosis (clear cut portal fibrosis expansion and/or longer septa) F3 Advanced Fibrosis (bridging of any degree with/or without regenerative nodules) F4 Cirrhosis (reorganization of hepatocyte to sinusoidal spaces)

  40. Control 0 DEN 4w 6w 8w 10w 12w 14w

  41. Control = CSAA CDAA 6 weeks 0 H&E Sirius Red

  42. 0

  43. 0 Rat 09: T90 = 2.22 min Stage 0: No fibrosis

  44. 0 Rat 16: T90 = 2.37min Stage 2

  45. 0 Rat 21: T90 = 3.17min Stage 3: Bridging

  46. 0 Rat 15: T90 = 4.41min; Stage 4 Bridging with extinction of architecture

  47. 0 Rat 19 four weeks of DEN treatmentmix of F2, F3, & F4 F2 fibrosis septa Entire Left & right lobes Portion of cludate lobe T90 = 3.9 min F3 bridging Portion of cludate lobe F4 cirrhosis Portion of cludate lobe

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