Facility IBA 18/9 Cyclotron Accelerates p and d. Facility GMP Grade Clean Room Automated Dispenser Synthera Rig FDG 07/11/2014

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1 Dr Chris Marshall Director Introduction to PET Positron Emission Tomography Positron is anti matter equivalent of the electron Isotopes that are proton rich can decay by emission of a positron Positron and electron undergo matter anti matter annihilation β + +β - 2 γ Introduction to PET Take molecule and attach a positron emitting radionuclide (E.g DOPA) Inject patient with tagged molecule Image gamma rays to get map of molecular distribution Acquire at different time points to get additional function information Genesis Built in 2010 Total cost 18.5 M provided by Welsh Government Business Case by Cardiff University Built to provide routine clinical services to Welsh NHS and support Welsh Life Science Industries IBA 18/9 Cyclotron Accelerates p and d Multiple Targets 18 F, 11 C, 13 N, 15 O Solid Target 89 Zr and 86 Y GMP Grade Clean Room Automated Dispenser Synthera Rig FDG Trasis AIO Rig F DOPA (Q4 2014) Fallypride (Q2 2015) GE Fastlab (funding in place) Amyloid Tau tracer (Q3 2015) E&Z Carbon 11 Rig 1

2 Quality Control Lab HPLC Gas Chromatography TLC MCA Endotoxin ph Meter PET CT Scanner Time of Flight 64 Slice CT O15 Water Generator Planning Laser Research 3 Hot Cells E&Z Rig R&D QC Lab Pre Clinical PET SPECT CT Pmod software Clinical Service Year COLORECTAL GYNAE HEAD & NECK Paediatric service for South West England started in March 2013 Epilepsy service started in November 2013 Private patient service available FDG F Choline in Prostate Cancer Amyloid Plaque imaging LUNG LYMPHOMA OESOPHAGEAL OTHER Grand Total Existing Research Multiple trials assessing response to novel therapeutic agents in cancer Why am I Here? GW 4 Collaboration Neuroimaging Research Strategy Multiple trials using F Choline in Prostate Cancer 2

3 GW 4 GW4 brings together the South West and Wales four leading, research-intensive universities. Bath, Bristol, Cardiff and Exeter Universities are collaborating through their research to address the key global challenges for the benefit of society and the economy. The collaborative strength of the GW4 gives a new and competitive edge not only in the UK, but internationally. With a combined turnover well in excess of 1bn, GW4 has a research power of significant scale. Building on existing collaborations, the Universities work together across all academic activity, opening up more opportunities to collaborate in common areas of shared facilities, learning, training, development and other resources. Neuroimaging Research Strategy Cardiff University aggressively pursuing developing Neuroimaging facilities CUBRIC II PETIC Tracer Pipeline F DOPA (late 2014) Fallypride(mid 2015) Tau (late 2015?) GABA (?) Glutamate (?) Neuroimaging Research Strategy Research Infrastructure Fund TRASIS All in One purchase funded ( 130k) F DOPA produced and validated for human use before 2015 Carbon 11 Infrastructure Methyl Iodide system commissioned to enable 11C labelled tracer ( 30k) Life Sciences Research Network Wales Funding to develop 18F Fallypride production obtained (83k) Available Q UK Dementia Platform HERMES Medical System funded ( 120k) GE Fastlab funded ( 130k) Agents Amyloid deposition central to Amyloid cascade hypothesis in aetiology of Alzheimer s Disease Considered an early event on the path to dementia but can also occur in normal aging Pathological studies cannot provide information about events early in disease process Cannot provide information about how amyloid, tau formation or neuronal loss are related. Imaging Agents 3 commercial agents available. All based on 11 C PiB compound by 18 F labelled. Cardiff licensed to image with these agents Can measure Amyloid plaque load in vivo Private patient service in place Not available on Welsh NHS but limited indications for NHS England Routine clinical indications Early signs of cognitive impairment and differentiation from normal aging 3

4 Agents is thought to be one of the earliest biomarkers in the progression of Alzheimer s disease Negative scans means there are few to no plaques in the brain so it is unlikely that AD is the cause of symptoms at the time of the scan. Positive scan does not diagnose AD but amount of plaque in the brain is similar to the amount seen in people with AD. This may also be seen in people with thinking or memory problems as well as in older people with normal thinking and memory Dementia with LewyBodies and Parkinson s Disease Dementia Increased uptake in DLB compared to controls Normal uptake in PDD Increased uptake could contribute to rapid progression of dementia in DLB May play a role in timing of dementia relative to motor symptoms in Parkinsonism in DLB and PDD Mild Cognitive Impairment Amyloid plaque imaging may have potential in identifying MCI subject at high risk for progressing to AD. Frontotemporal Dementia (FTD) Difficult to distinguish clinically between AD and FTD. As amyloid deposition not a feature of AD, Amyloid plaque imaging may have a role in differentiating AD and FTD. Tau Hyperphosphorylationof the Tau protein leading to formation of neurofibrillary tangles (NFT) is a common feature in a wide range of neurodegenerative diseases known as Tauopathies. Include AD, FTD Tau tracers in PET target Tau tangles allowing in-vivo quantification of Tau pathology Tau Basic Research Non Invasive longitudinal tracking of Tau pathology Longitudinal assessment of behaviour as a function of Tau pathology Determination of pharmacokinetic properties Development of theoretical models regarding progression of Tau pathology Development of novel radiopharmaceuticals to measure Tau Tau Clinical Research Early diagnosis Differntialdiagnosis Follow up of cognitive decline as a function of Tau pathology progression Monitoring of treatment effectiveness of novel anti Tau and associated therapies Development of theoretical models regarding tau pathology progression 4

5 Tau FDG in Dementia FDG able to measure glucose metabolism in vivo In early AD, FDG demonstrates glucose metabolic reduction in parietotemporalassociation cortices, posterior cingulate and precuneus regions In advanced AD, hypometabolicregions spread to frontal association cortices. FDG in Dementia MCI cognitive impairment is a heterogeneous pathology whilst MCI due to AD shows same pattern as early AD. FDG in Dementia FDG in Dementia F DOPA and Fallypride Clinical Applications Glioma Parkinson s Schizophrenia Addiction Attention Deficit Hyperactivity Disorder 5

6 Glioma F DOPA is a radiolabelled amino acid and shows similar behaviour to 11 C Methionine Clinical Applications at Diagnosis Determining degree of malignancy Assessing prognosis Guidance for biopsy Determining tumour extent for therapy planning Glioma Clinical Applications After Therapy Monitoring Response to Therapy Differentiation between Recurrence and Necrosis In Vivo Assessment of the Dopaminergic System With PET it is possible to image and assess the function of the pre and post synaptic sites. F DOPA to image pre-synaptic dopamine function by measuring striatal aromatic amino acid decarboxylase activity Fallyprideto image D2/3 post synaptic dopamine function FDOPA Can be used in the diagnosis of Parkinson Disease in the same manner to DaTSCAN. PET enables accurate quantification of Dopamine function not available in conventional SPECT Monitor effectiveness of therapy Monitor progression of disease SPM allows assessment of extrastriatal function as well Neurology 2013, 81(13); Patel et al Benefits of PutaminalGDNF Infusion in are Maintained after GDNF Cessation Goal of therapy is to increase production of dopamine in the striatum. Implantation of fetal or engineered stem cells Infusion of growth factors Injection of viruses engineered to express dopaminergic genes. 6

7 Post Synaptic D2/3 receptor availability can be assessed with 18F Fallypride Similar to 11C Raclopride Mild increase in uptake in early PD. Uptake is inversely correlated to 18F DOPA uptake in early disease. As disease progresses, D2/3 function normalises in the putamen and decreases in the caudate. In Vivo Assessment of the Dopaminergic System PET can also be used to measure Availability of Presynaptic dopamine transporters from the synaptic cleft The density of VMAT2 Striatal D1 receptor binding PETIC not currently able to offer this functionality Schizophrenia Thought dopaminergic dysfunction underlies the development of psychosis. Imaging studies have shown increase dopamine release and elevated dopamine synthesis capacity in patients with Schizophrenia Thought to cause greater stimulation of D2 receptors. Many antipsychotics primary target is antagonism of striatal D2 receptors Addiction Multiple studies suggest rewarding properties of misused drugs relate to their ability to provoke Dopamine release. Able to investigate Intoxication Craving Loss of Inhibitory Control and Bingeing Withdrawl and Relapse Attention Deficit Hyperactivity Disorder Dopamine Transporter (DAT) responsible for presynaptic reuptake of dopamine Majority of studies show increase of DAT Density in ADHD Patients Increased DAT indirectly activates D2 receptor activity which enhances attention and engenders stimulation Studies also show increased uptake in D2 receptors Future Possibilities GABA Receptor Imaging Glutamate Receptor Imaging H 2 15 O perfusion imaging 7

8 Why am I Really Here? Increase awareness of our capabilities Seeking users of our new infrastructure Seeking collaborations for research projects What would Exeter Neuroscience want from PETIC in the future? Research Facilities at PETIC Research Radiochemistry lab Research QC lab Gamma Medica PET/CT/SPECT Pre clinical Scanner Research Projects at PETIC Zr-89 a long lived isotope for bio-macromolecule tagging Antibodies exist in the blood pool for several days making them unsuitable for labelling with traditional short lived PET isotopes Zr-89 has a 3.25 day half life Aluminium solid target holder (coin) with Y-89 target foil (150 µm). Research Projects at PETIC Zr-89 a long lived isotope for bio-macromolecule tagging 1 day p.i. 3 day p.i. 7 day p.i. Mouse Prostate Cancer model (PC3) van Rij et al., J Nucl Med 2011; 52:1601 Research Projects at PETIC Reporter genes for tracking genetically engineered cells Thymidine Kinase enzymes (tk) trap thymidine like molecules in cells by phosphorylating them. X Thymidine Kinase HSV-tk tumour normal tumour 18 F-FIAU Herpes simplex virus Thymidine Kinase Tjuvajev, J. G. et al. J Nucl Med 43, (2002). 8