ZW GMP Lab for production of PET tracers for clinical and translational research Luc Mortelmans, Guy Bormans, Koen Van Laere, Christophe Deroose, Alfons Verbruggen, Johan Nuyts

Tracks molecules in the body by external detection of gamma rays emitted during decay of short-lived positron emitting radionuclides positron emission tomography (PET) 1. Tracer injection + distribution throughout the body 2. External detection of gamma rays (PET camera) 3. Images representing tracer distribution are reconstructed

positron emission tomography (PET) Modelling of kinetic analysis of PET data provides parametric maps e.g. in vivo receptor occupancy Time-activity curves Plasma input curve Radiometabolite quantification Kinetic modelling Binding potential B max /K d

PET tracer production: layout Radiosynthesis incorporation of radionuclide in target molecule Purification and formulation Prepar. HPLC, sterile membrane filtration QC HPLC, GC, pH, sterility, pyrogens … Radionuclide production Cyclotron irradiation (fluorine-18, carbon-11) Generator (gallium-68)

PET tracer production: a race against time radionuclideHalf-life Fluorine min Gallium-6868 min Carbon-1120 min Cyclotron production radiosynthesis Purification & formulation QC Scanning & Sample processing

Why cGMP for PET tracers? Radiopharmaceutical for human use Intravenous administration For clinical trials: cGMP required

PET tracers for clinical research and cGMP: legal issues Belgian Royal Decree May 7th 2004 experiments on the human person CHAPTER XIII. – § 3 a …in the case of investigational medicinal products manufactured in Belgium, that each batch of medicinal products has been manufactured and checked in accordance with the principles and guidelines for good manufacturing practices EC Directives 2003/94/EC principles and guidelines of good manufacturing practice of medicinal products and investigational medicinal products for human use

PET tracers for clinical research and cGMP: legal issues Eudralex volume 4: Good manufacturing practices

Requested infrastructure infrastructure/equipment € 2,380,000 personnel € 238,000 maintenance contracts € 115,000 Total budget : €2,733,840 Radiolabelling modules € 1,071,000 hot cells € 850,000 quality control equipment € 457,000

Proposed financing Hercules foundation € 1,984,000 GE € 150,000 Siemens € 150,000 Johnson&Johnson € 200,000 Merck € 250,000 Total support from companies:€ 750,000 (27%)

Project fits in the strategy of K.U. Leuven - MoSAIC: “Molecular Small Animal Imaging Centre” - Radiopharmacy lab - Investment in building GMP lab - State of the art clinical pharmacology lab - Medical Image Research Center (MIRC) - Flanders “PET net” (network)

4 synthesis hotcells, 1 dispensing hotcell for FDG 6 synthesis hotcells, 1 dispensing hotcell for contract research New building level 01 FDG + Contract research

Nuclear Medicine Cyclotron MoSAIC Radiopharmacy Lab University Hospital Leuven Nuclear Medicine

“MIRACLE” (Molecular Imaging Research & Application Center Leuven) From bench to bedside

Antwerpen, VUB, KUL, RUG, UCL, ULG, ULB (UNIV – 7) Hasselt, Charlerloi, Kortrijk, Bodet, Antwerpen, Mont-Godinne (NIET-UNIV – 6) University Hospital Leuven Nuclear Medicine

Onco-imaging clinic & research Clinical research Medical Physics Radiopharmaceutical chemistry Cardiology A) Diagnosis - Lung tumours - GI tumours - Lymphoma - Sarcoma (GIST) - Breast tumours - Response evaluation early clinical trials B) Therapy Infection and inflammation Gene expression Reconstruction Kinetic modelling Image registration SPECT 99m Tc labeling 123 I labeling PET 18 F labeling 11 C labeling Data-analysis PET microPET SPECT microSPECT Bioluminiscense MRI microMRI Neurology & psychiatryRadiology Oncology

Nuclear neuro-imaging research Clinical research Medical Physics Radiopharmaceutical chemistry Cardiology Oncology Infection and inflammation Gene expression Reconstruction Kinetic modelling Image registration SPECT 99m Tc labeling 123 I labeling PET 18 F labeling 11 C labeling NeuroImaging Data-analysis PET microPET SPECT microSPECT Bioluminiscentie MRI microMRI Neurology & psychiatry - Movement disorders - Epilepsy - Dementia - Brain Tumours - Eating disorders - Anxiety and mood disorders Radiology

Experimental PET-CT Biograph 16-HiRez (contract research 2005)

MIRACLE : multidisciplinary platform Medical Physics Radiopharmaceutical chemistry Oncology Gene expression Reconstruction Kinetic modelling Image registration SPECT 99m Tc 123 I PET 18 F 11 C Data-analysis Neurology/psychiatry Stem cell research Cardiology Clinical Pharmacol ogy - Recruitment (esp. HV) - Screening - Drug admin - PK sampling -... Clinical Divisions - Patient recruitment Infection-inflammation Clinical nuclear medicine Radiology

drug review/ market Improved diagnosis/ therapy Position & Role of MoSAIC IMAGING SOLUTIONS Improved insights & novel hypotheses Novel diagnostic & therapeutic strategies imagingclinicalLife sciences core partners peripheral partners ‘basic’ research preclinical development clinical research MoSAIC Omics

PET MRI BLI CT US Dedicated small animal imaging equipment Clinical imaging equipment adapted to small animal scanning: SPECT MoSAIC multimodality imaging facility (2007)

Translational molecular imaging technique positron emission tomography (PET) microPET scannerclinical PET scanner Rat model of Parkinson’s disease imaging of dopamine transporter Patient with PDnormal

PET in drug development Identify Targets Find Leads Toxicology Clinical Trials Regulatory Approval Time (Years) $ 800 MM - $1.6BN 5317 Research Development Refine Leads LaboratoryClinic $$$ Slide courtesy of R Hargreaves, MSD Accept or Reject a Candidate or Hypothesis

PET in drug development PET provides -early clinical target validation -early clinical target occupancy data as a funtion of dose as a function of time p.i. development of PET probes for new targets in parallel to drug development by all major pharmaceutical companies (MSD, Novartis, J&J, SKB, Roche,…)

Therapeutic drugs and PET tracers Therapeutic drug PET tracer Bio-availability after oral dosing +++- Plasma half-life>6 h<30 min Toxicity+++- High affinity++++ High selectivity++++ Fast and efficient radiolabelling with 11 C or 18 F -+++

PET tracers for clinical research and cGMP: legal issues Eudralex volume 4: Good Manufacturing Practices Production cell class “C” air Aseptic activities Class “A“air

ISO-certification Nuclear Medicine (2005)

Center for Clinical Pharmacology Clinical Research Unit (1) Facilities hotel accommodation: –20 beds for overnight stay –sanitary facilities (3 showers) –2 recreational areas (internet access, TV, video, …) research laboratories (4 laboratories; 2 temperature controlled) laboratory for sample processing medication room secretary and offices meeting room / monitoring office archive

Center for Clinical Pharmacology Clinical Research Unit: study types

MoSAIC Molecular Small Animal Imaging Center Animal models of human disease D C A: µPET B: µCT C: µUS D:µSPECT E: µMRI F: BLI 380 m² Imaging 320 m² Support

3 synthesis hotcells 1 dispensing hotcell for FDG 10 synthesis hotcells for research 1 glovebox for dispensing Upgrade level 0: FDG (temporarily) + research 1 LAF- cabinet Sas