LifeLife SciencesSciences atat thethe CyclotronCyclotron CenterCenter ofof thethe SlovakSlovak RepublicRepublic

Dušan PODHORSKÝ - Peter KOVÁČ - Fedor MACÁŠEK GeneralGeneral BackgroundBackground EU PHARE

The Trilateral Region of Austria-Hungary-Slovakia is a rapidly emerging high growth region with immense potential for development j lti

s k n i L a e Ar a v a l s i t a r B Milestones

Government's resolution to build the cyclotron 1996 laboratory within the Slovak Institute of Metrology in Bratislava, using the liabilities of the Russian Federation and the facilities of the Joint Institute of Nuclear Sciences, Dubna. Co-operation project with IAEA "Radiochemical 1997 facilities for production of medical radionuclides" was launched. Government's resolutions on the $US 118 mil. 1999 planning and financing scheme for the years 2000- 2006 were approved. A general contract on the keyturn realisation of the CC 1999 SR between the Slovak Office of Standards, Metrology and Testing and the ATOMENERGOEXPORT (RF) was signed. TheThe CyclotronCyclotron CenterCenter ofof thethe SlovakSlovak RepublicRepublic ProjectProject A state run scientific center and production facility ensuring • the basic and applied research in nuclear physics, chemistry, biology and medicine, • production of radionuclides and radiopharm- aceuticals, and • applications of heavy ions and electrone accelerator technologies in medicine and material science. 1. PET Centrum with cyclotrone Cyclone 18/9 (IBA, Belgium), production of PET radiopharmaceuticals and a nuclear medicine clinics, based on the reconstruction of existing building (Pavilion „I“) - to be finished in May 2004. 2. New pavilion “J” with DC72 cyclotron (JINR Dubna, RF), dedicated for production of SPECT and therapeutical radiopharmaceuticals and hadron therapy facility - to be completed in 2006. CCyycclloottrroonn mmeeddiiccaall rraaddiioonnuucclliiddeess diagnostic therapeutic SPECT EZ (Auger) PET α β- 3 MeV D 15O 11 13 18 10Cyclone MeV H 18/9 + C, N, F 18 MeV H + 64Cu, 68Ga,75Se,76Br, 86Y, 9 Pavil.MeV „I“D 94mTc, 103Pd, 124I

20-30 MeV H + 34mCl, 51Cr, 51Mn, 57Co, 67Cu, 68 67 77 81 81 111 DC 72 Ge, Ga, Br, Rb- Kr, In, 123I , 201Tl, 212,213Bi Pavil. „J“ 40-60 MeV He + 38K, 86Y,195mPt, 211At ... Milestones PET Center Bratislava (Pavilion “I” reconstruction) April 2003 – November 2004

DC-72 Building (Pavilion “J” building) 2004 – 2006 The Slovak Institute of Metrology - Cyclotron Center site Current financial status

• Deblocation of the Russian Federation debt to the Slovak Republic (94 %) • State budget of the Slovak Republic (3 %) • IAEA (3 %) Legislation and Safety Issues Regulatory meeting point at the stage of construction approval • The new Radiation Safety Act (Vyhl.12/2001 Z.z.), and a l% (!) limit for contribution to the public radiation doses • No exemptions for the radioactive drugs production and distribution from the State Institute of Drug Control (ŠÚKL), the same requests as to sterile production of other intravenous pharmaceuticals ! Structure of quality management in the RP production Quality Management)

Pharmacopoeia Quality Assurance) Health Inspection and Environmental Good Manufacturing Engineering Practice (cGMP)

Quality Control, Good Practice of Control Laboratories (GPCL) Pharmaceutical Legislation

• Slovak Republic Health Care Act 272/1994 • European Pharmacopoeia / Slovak Pharmacopoeia • EC Directorate III Rules Governing Medicinal Products in European Union 1998 • EEC Council Directives 99/11 and 99/12 • Pharmaceutical Inspection Convention (PIC) • Pharmaceutical Inspection Co-ordination Scheme (PIC/S) • International Conference on Harmonization Good Manufacturing Practice for Active Pharmaceutical Ingredients (ICH Q7A GMP API) • Slovak State Institute for Drug Control Guidance PETPET CenterCenter Oncological Institute of St.Elisabeth

• 18F-FDG import from the Institute of Nuclear Physics in Prague •• 3000 patients since August 2001 ECAT EXACT HR+ (Siemens) Central Military Hospital Ružomberok

• cardiological investigations • 99mTc and 18F apllications

MILLENIUM VG HawkEye (GE) PlannedPlanned PETPET RadiopharmaceuticalsRadiopharmaceuticals

Radiopharmaceutical Applications Prod- uction time % [18F]-Fluorodeoxyglucose glucose metabolism in 65 (FDG) tumours, myocardium and brain, Alzheimer disease L-3,4-Dihydroxy-6-[18F]- aminoacids transport in 13 fluorophenylalanine (DOPA) brain and tumours, Parkinson‘s disease [18F]-Fluoride sceleton 5 [11C]-Raclopride dopamine receptor ligand 10 [15O]-Water myocardial blood flow 2 [13N]-Ammonia regional blood flow 5 CycloneCyclone 18/918/9 radionuclideradionuclide productionproduction programprogram

Nuclide t Reaction Activity EOB Radio-pharmaceutical T1/2 hrs GBq min 18F- 2x3 18O(p,n) 110 [18F]FDG 110 18 2 20 18 F2 Ne(d,α) 4 [ F]DOPA 13 0.3 16 13 N 10 O(p,α) 4 [ N]NH3 11 1 14 11 C 20 N(p,α) 40 [ C]CH3I 15 0.5 14 15 O 2 N(d,n) 11 [ O]H2O Cyclone 18/9 (IBA) in the vault Production and Quality Control from IAEA LC/MS analyser Agilent 1100

Tracerlab FX 18F- FDG synthesis module

Tracerlab FX 18F- DOPA 11 synthesis module Tracerlab FX C methylation module HotHot cellscells TemaTema SinergieSinergie PET Center Hot Cells

21 m Capillary ducts from targets to hot cells t

O Nb target target O Nb O Ag target target O Ag target 18 18 2 2 2 O target 16 +O 2 2 deuteron targe deuteron 2 H N Ne target Ne deuteron +O Small H Large H 2 20 N CYCLONE 18/9 [15O]O 13 18 18 11 2 [ N]NH4OH [ F]HF/H20 [ F]F2 [ C]CO2 R&D PTFE ID 0.8 mm SS ID 0.7 mm SS ID 1.75 mm black nylon 1/8” PTFE ID 0.8 mm (5x2 capillars) (2 capillars) (1 capillar) (2 tubes) (2 capillars)

18 18 11 15 13 "C" F-FDG 18F spare F-DOPA C-raclopride [ O]H2O NH4OH research products synthesis synthesis or synthesis synthesis module module synthesis sampling module 11C gaseous module module modules methylation T013a SMC 1/70 T024 SMC 2/70 T020 IAEA T022 SMC 2/70 T026 SMC 2/70 T025 SMC2/70 T122 WHM T117 LFH2/20

13 gas pipe 18 11 [15O]H O [ N]NH4OH F dispensing unit C dispensing unit 2 liquid pipe "A" container to clinics transport PET zone border T013 IAEA T019 NMC 1/50 scanner Pre-clinical studies PET Center Nuclear Medicine Clinics microPET

SlovakSlovak AcademyAcademy ofof Sciences:Sciences • endocrinology and pharmacokinetics • radiopharmaceuticals pre-clinical studies CyclotronCyclotron CenterCenter DC72DC72 designdesign

• isochronous cyclotron • ion beams from H (maximum energy up to 72MeV) to Xe (maximum energy 2.7MeV/nucleon) • maximum beam current from 100µA for H- down to 1µA for 129Xe18+ • ions are extracted from the accelerator chamber in two opposite directions DC-72 model of magnit DC-72 ECR source DC-72 correction coil DC-72 completion ProductionProduction

• Iodine-123 radiopharmaceuticals • 123I labeled biospecific macromolecules (peptides, antibodies, ligands of cell receptors, monitors of gene expression) PlannedPlanned 123II RadiopharmaceuticalsRadiopharmaceuticals

Radiopharmaceutical Applications Prod- uction time % Sodium iodide general labeling 37 Meta-iodobenzylguanidine crest tumors, 35 (MIBG) feochromocytosomes and neuroblastomes, uptake in myocardium 2-β-Carbomethoxy-3-β-(4- dopamine and serotonine 7 iodophenyl)tropane (β-CIT) transporters Iodo(heptadeca)penta-decanoic cardiomyopathies 7 acid (IPPA) Iodobenzamide (IBZM) neuroreceptor 7 Iodohippurate (Hippuran) kidney function 7 PilotPilot productionproduction

• Target-oriented (biospecific) astatine-211 therapeutic radiopharmaceuticals DubnaDubna 7272 MeVMeV cyclotroncyclotron radiopharmaceuticalsradiopharmaceuticals programprogram nuclide activity radiopharmaceuticals GBq/day 123I 50-100 NaI capsules, MIBG, β-CIT, IPPA, IBZM, proteins 81Rb 30-70 Kr-81 generators 211At 1-2 proteins, antibodies various universal solid target

IonIon beamsbeams applicationsapplications

• Proton therapy of eyes • Boron neutron capture (BNC) therapy • Physical Laboratories PhysicalPhysical laboratorylaboratory

ION BEAM ANALYSIS •HI-RBS • ERDA • HE-PIXE •CPAA ION BEAM MODIFICATION OF MATERIALS• Polymers irradiation • Radiation hardness DC72 for Life Sciences

81RbRb 123II IBA solidsolid targettarget IBMM

Proton BNC therapy therapy IBA auxiliary „D“ R&D GMP zone 480 m2 pneumatic post

R&D productionproduction cleanclean classroomsrooms„A“ rooms quality control

auxiliary „D“

quality control packing Class „C” laboratories for SPECT RP flexible approach 3x24 m2 from class „C“ to „D“ and vice versa

corridor “D” corridor “C” Class „C” laboratories for SPECT RP dispensing „A“ auxiliary „C“ synthesis „C“

corridor “D” corridor “C” Class „C“ alpha laboratories

alpha lab biochemical analysis

27 m2

64 m2

pneumatic post

solid target On the boarders of sciences AcceleratorAccelerator MetrologyMetrology forfor MedicineMedicine • Metrology of ion beams • Standards for short-lived radionuclides • Microdosimetry of radiopharmaceuticals MicroMicro-- andand NanotechnologyNanotechnology

• Laboratory-on-chips • Microsynthesis of radiopharmaceuticals International Design Experts

• Dr.V.E.BECHTOLD, Karslruhe • Dr.P.KOPECKÝ, Prague • Prof.G.BEYER, Geneva • Dr.R.M.LAMBRECHT, Brookhaven • Dr.A.CHUMBALOV, Dubna • Dr.J.LINCKE, Dresden • Dr.J.C.CLARK, London • Dr.F.MELICHAR, Řež • Dr.S.N.DMITRIEV, Dubna • Dr.Y.OGANESIAN, Dubna • Dr.G.G.GULBEKIAN, Dubna • Dr.D.SCHLYER, Brookhaven • Prof.G. HÖR, Frankfurt • Dr.J.ŠTURSA, Řež • Prof.T.IDO, Tohoku • Dr.F.TARKÁNYI, Debreczen • Dr.Y.JONGEN, Louvain-la- • Prof.W.VAALBURG, Groeningen Neuv • Dr.H.VERA-RUIZ, IAEA • Dr.B.O.KNOOP, Hamburg International Cooperation

• JINR Dubna, Russian Federation • NIH Bethesda, USA • TESLA Association, Serbia • Institute of Nuclear Physics, Czech Academy of Sciences • Institute of Nuclear Research a.s., Czech Republic • Nuclear Centre „DEMOKRITOS“, Greece Internal Cooperation • Slovak Institute of Metrology • Slovak Technical University Faculty of Electroengineering and Informatics • Comenius University Faculty of Mathematics, Physics and Informatics Faculty of Naturals Sciences Pharmaceutical Faculty • Slovak Academy of Sciences Institute of Physics Institute of Experimental Pharmacology Institute of Endocrinology „The Cyclotron Center of the Slovak Republic project is state-of-the-art and that has great potential for research, education and exploitation in nuclear medicine, atomic and nuclear physics, technological and industrial applications and advanced radiotherapy“

International Scientific-Technical Committee of CC SR (V.Bechtold, Y.Jongen, R.Mach, R.Oganessian, G.Ryckewaert), April 2002

„Within three years one of the most modern cyclotrone center is to be built in Bratislava“

V.V.Kozlov, Director General of ATOMENERGOEXPORT, October 2002