micro PET Experiences with Small Animal PET Imaging

micro. PET Experiences with Small Animal PET Imaging Simon R. Cherry, Ph. D. Supported by NCI grants CA 69370 CA 74036 and DOE contract FC 03 -87 -ER 60615 Crump Institute for Biological Imaging Dept. of Molecular and Medical Pharmacology UCLA School of Medicine, Los Angeles, California Crump Institute for Biological Imaging

Outline • PET Basics • motivation for small animal PET • design & performance of a small animal PET scanner • applications for small animal PET Crump Institute for Biological Imaging

Positron Emission Tomography e+ e+ positron scatters in tissue losing energy nucleus e+ 511 ke. V e+ yes coincidence ? e– e+ annihilation 511 ke. V Crump Institute for Biological Imaging

Positron-Emitting Radionuclides Isotope Halflife + fraction Max. Energy range(mm) production C– 11 20. 4 mins 0. 99 0. 96 Me. V 0. 4 mm cyclotron N– 13 9. 96 mins 1. 00 1. 20 Me. V 0. 7 mm cyclotron O– 15 123 secs 1. 00 1. 74 Me. V 1. 1 mm cyclotron F– 18 110 mins 0. 97 0. 63 Me. V 0. 3 mm cyclotron Cu– 62 9. 74 mins 0. 98 2. 93 Me. V 2. 7 mm generator Cu-64 12. 7 hours 0. 19 0. 65 Me. V 0. 3 mm cyclotron Ga– 68 68. 3 mins 0. 88 1. 83 Me. V 1. 2 mm generator Br-76 16. 1 hours 1. 00 1. 90 Me. V 1. 2 mm cyclotron Rb– 82 78 secs 0. 96 3. 15 Me. V 2. 8 mm generator I– 124 4. 18 days 0. 22 1. 50 Me. V 0. 9 mm cyclotron Crump Institute for Biological Imaging

PET-labeled Probes for Biological Imaging cyclotron 11 C, 13 N, 15 O, 18 F hemodynamic parameters (H 215 O, 15 O-butanol, 11 CO, 13 NH 3. . . ) substrate metabolism(18 F-FDG, 15 O 2, 11 C-palmitic acid. . ) protein synthesis (11 C-leucine, 11 C-methionine, 11 C-tyrosine) enzyme activity (11 C-deprenyl, 18 F-deoxyuracil. . . ) drugs (11 C-cocaine, 13 N-cisplatin, 18 F-fluorouracil. . . ) receptor affinity (11 C-raclopride, 11 C-carfentanil, 11 C-scopalamine) neurotransmitter biochemistry (18 F-fluorodopa, 11 C-ephedrine. . . ) gene expression (18 F-penciclovir, 18 F-antisense oligonucleotides. . . ). . . . . PET can detect and image sub nanomolar levels of these tracers in vivo Crump Institute for Biological Imaging

Human Whole-Body PET Scanners 18 FDG - transaxial sections through brain Siemens ECAT EXACT HR+ 20, 000 scintillator detectors ring diameter ~ 80 cm 4 mm (64 µL) spatial resolution (typically 6 -12 mm in clinical practice) Crump Institute for Biological Imaging

Time Course of 18 F-FDOPA in the Brain 0. 0 mins 4. 5 mins 40 mins 0. 75 mins 1. 25 mins 1. 75 mins 2. 25 mins 2. 75 mins 7. 5 mins 10. 5 mins 13. 5 mins 20 mins 30 mins 60 mins 75 mins 50 mins 95 mins 115 mins Crump Institute for Biological Imaging

Tracer Kinetic Modeling striatum cerebellum • Simplified model for FDOPA kinetics in striatum • Rate constants K 1, k 2, k 3 & k 4 can be estimated using measured PET time activity curves and blood input function. K 1 plasma FDOPA k 2 tissue FDOPA k 3 FDA and its metabolites k 4 clearance of 18 F label to plasma FDOPA = [18 F]fluoro. DOPA Crump Institute for Biological Imaging

Why Small Animal Imaging? • in vivo in vitro • non-destructive - repeat studies in the same animal • can efficiently survey whole animal • rapid in vivo screening? • provides bridge from animal studies to human studies • better decisions sooner! Crump Institute for Biological Imaging

In Vivo Small Animal Imaging Anatomic Physiologic Metabolic Molecular optical imaging x-ray CT MRI PET/SPE CT MR Spectroscopy f. MRI ultrasound Crump Institute for Biological Imaging

Which Imaging Technique? • • • what do you want to measure? spatial resolution (µm or mm? ) temporal resolution (ms or mins? ) sensitivity (m. M or n. M? ) field of view (striatum or whole animal? ) • what’s available Crump Institute for Biological Imaging

micro. PET • 30 detector modules • 1920 detector elements • ring diameter: 172 mm • axial field of view: 18 mm • spatial resolution: 1. 8 mm (6 µL) • sensitivity: 200 cps/µCi (CFOV) Crump Institute for Biological Imaging

Small Animal PET Scanner Development • • • micro. PET (UCLA/Concorde Microsystems) HIDAC (Oxford Positron Systems) SHR-7700 (Hamamatsu, Japan) Sherbrooke Animal PET (Sherbrooke, Canada) RATPET (MRC Hammersmith) Tier. PET (Jülich, Germany) YAP-PET (Ferrara, Italy) MAD-PET (Munich, Germany) ANI-PET (Montreal, Canada) Crump Institute for Biological Imaging

micro. PET images baby monkey brain phantom (25 cc) Siemens EXACT HR+ micro. PET Crump Institute for Biological Imaging

18 F-FDG Whole Body Rat Study micro. PET Crump Institute for Biological Imaging

18 F-FDG Rat Heart micro. PET Crump Institute for Biological Imaging

Micro. PET images of rat myocardium (13 NH 3) Short Axis Vertical long Axis Baseline Occlusion Reperfusion Horizontal long Axis Polar Map T. Kudo, A. J. Annala and H. Schelbert Crump Institute for Biological Imaging

Comparison of Metabolic Images FDG FCx Caud/Put PCx Thal TCx Bs autoradiography FDG micro. PET Amy Moore, David Hovda, Simon Cherry UCLA Crump Institute for Biological Imaging & Division of Neurosurgery

micro. PET Quantitative FDG-micro. PET 120 autoradiography micro. PET autoradiography 100 80 60 CMRGlc ( mol/100 g/min) 40 20 Amy Moore, David Hovda, Simon Cherry UCLA Crump Institute for Biological Imaging & Division of Neurosurgery 0 Frontal Cx Caudate/ Putamen Parietal Cx Thalamus Crump Institute for Biological Imaging

CMRGlc Following Traumatic Brain Injury Baseline 2 days 75 post-injury CMRGlc 5 days 0 post-injury 10 days post-injury Rat #383 Amy Moore, David Hovda, Sheri Osteen, Simon Cherry UCLA Crump Institute for Biological Imaging & Division of Neurosurgery

Rat Striatal Dopamine System Imaged with micro. PET [C-11]WIN 35, 428 DA Transporter Binding [C-11]Raclopride DA D 2 Receptor Binding Control Lesioned Striatum Unilateral 6 -Hydroxydopamine Lesioned Striatum Dan Rubins, Goran Lacan, Simon Cherry, and. William Melega Crump Institute for Biological Imaging

Mouse 11 C-WIN Brain: 35, 428 Time Activity curve 30 g mouse transverse brain section 180µCi of 11 C-WIN 35, 428 (0. 018µg) Crump Institute for Biological Imaging

Micro. PET Tumor Imaging 64 Cu-DOTA anti-CEA Minibody • Athymic mouse with LS 174 T (CEA+) and C 6 (CEA-) xenografts • Injected with 70 µCi 64 Cuanti-CEA minibody (engineered antibody fragment, sc. Fv-CH 3 ) • Scanned 12 hr post injection C 6 LS 174 T Liver Data courtesy of Anna Wu (UCLA and City of Hope) Crump Institute for Biological Imaging

Imaging Gene Expression by PET Crump Institute for Biological Imaging

PET in Drug Development • direct radiolabeling of drug – biodistribution and pharmacokinetics • binding/competition studies – dosing and pharmacodynamics • indirect markers – pharmacodynamic effect on secondary marker (e. g. metabolism or blood flow) Crump Institute for Biological Imaging

Positron Emission Tomography Advantages: vast range of biological processes can be measured quantitatively sensitivity can be in n. M to p. M range whole animal biodistribution and kinetics Disadvantages: relatively coarse spatial (~mm) and temporal (~mins) sampling synthesis of radiolabeled compounds can be a bottleneck little or no anatomical information Crump Institute for Biological Imaging

MR Compatible PET System Concept Animal MR system PET Detectors MR Receiver Coil Crump Institute for Biological Imaging

Prototype MR Compatible PET Scanner 56 mm ring diameter 72 2 x 2 x 25 mm LSO scintillators optical fibers PMT’s Crump Institute for Biological Imaging

Experimental Setup Prototype MR compatible PET scanner inside 1. 5 T clinical MR Crump Institute for Biological Imaging

Simultaneous In Vivo Imaging 200 g Rat - 18 F-FDG Brain Study PET MRI 1. 3 m. Ci 18 F-FDG TE=12 msec, TR=280 msec imaging time 30 mins continuous 75 secs slice thickness ~ 2 mm acquisitions during PET study slice thickness 4 mm Crump Institute for Biological Imaging

Rapid In Vivo Drug and Genetic Screening with PET and CT combined anatomical & molecular imaging for use with 18 F-labeled ligands or secondary markers such as 18 F- FDG conveyor belt throughput of >20 mice per hour sophisticated bioinformatics to assist in analysis micro. CT micro. PET Crump Institute for Biological Imaging

References Chatziioannou AF, Cherry SR, Shao Y, Silverman RW, Meadors K, Farquhar TH, Pedarsani M, Phelps ME. Performance evaluation of micro. PET: A high resolution LSO PET scanner for animal imaging. J Nucl Med 40: 1164 -1175 (1999). Gambhir SS, Barrio JR, Herschman HR, Phelps ME. Assays for Non-Invasive Imaging of Reporter Gene Expression. Nuclear Medicine and Biology, 26: 481 -490 (1999). Mac. Laren DC, Gambhir SS, Satyamurthy N, Barrio JR, Sharfstein S, Toyokuni T, Wu L, Berk AJ, Cherry SR, Phelps ME, Herschman HR. Repetitive, Non-invasive Imaging of the Dopamine D 2 Receptor as a Reporter Gene in Living Animals. Gene Therapy, 6: 785 -791 (1999). Gambhir SS, Barrio JR, Phelps ME, Iyer M, Namavari M, Satyamurthy N, Wu L, Green LA, Bauer E, Mac. Laren DC, Nguyen K, Berk AJ, Cherry SR, Herschman HR. Imaging Adenoviral-Directed Reporter Gene Expression in Living Animals with Positron Emission Tomography. Proc Natl Acad Sci (USA), 96: 2333 -2338 (1999). Crump Institute for Biological Imaging

Acknowledgments Imaging Sciences Lab: Andrew Goertzen Andrew Wang Daniel Rubins Arion Chatziioannou Yiping Shao Yuan-Chuan Tai Robert Silverman Randal Slates Niraj Doshi Collaborators: Richard Leahy (USC) Jinyi Qi (LBNL) Concorde Microsystems Inc. UCLA: Sam Gambhir Harvey Herschman Michael Phelps Amy Moore David Hovda Harley Kornblum Heinrich Schelbert William Melega Takashi Kudo Alexander Annala Anna Wu Crump Institute for Biological Imaging