NUCLEAIRE BIOMEDISCHE
BEELDVORMING
INHOUDSOPGAVE
1.1 Wat is nucleaire biomedische beeldvorming? ........................................................................................... 5
1.2 SPECT (single photon emission computerized tomography) ..................................................................... 5
1.2.1 Humaan SPECT....................................................................................................................................... 5
1.2.1.1 Nucleaire aspect ........................................................................................................................... 5
1.2.2 Small animal SPECT ................................................................................................................................ 6
1.3 PET (positron emissie tomografie) ............................................................................................................. 6
1.3.1 Humaan PET........................................................................................................................................... 6
1.3.2 Small animal PET .................................................................................................................................... 7
2.1 Radiofarmaceutica ..................................................................................................................................... 8
2.2 Ontwikkeling van radiofarmaceutica ......................................................................................................... 8
2.2.1 Bepaling van het target ......................................................................................................................... 8
2.2.2 Vehicle, vector or targeting molecule ................................................................................................... 9
2.2.3 Keuze van radio-isotoop ........................................................................................................................ 9
2.2.3.1 Radiofarmaceutica voor diagnose ................................................................................................ 9
2.2.3.2 Radiofarmaceutica voor therapie ............................................................................................... 10
2.2.3.3 Beschikbaarheid van het radio-isotoop ...................................................................................... 10
2.2.4 Radiolabeling en optimalisatie van radiolabeling ................................................................................ 11
2.2.5 Zuivering van precursor en ongebonden radiolabel ............................................................................ 12
2.2.6 Steriele formulering en quality control van RF .................................................................................... 12
2.2.7 In vitro evaluatie .................................................................................................................................. 13
2.2.8 In vivo evaluatie ................................................................................................................................... 13
2.3 Vereisten voor radiofarmaca ................................................................................................................... 13
2.4 RF voor beeldvorming in de oncologie .................................................................................................... 14
2.4.1 Glucose metabolisme: 18F-fluorodeoxyglucose ................................................................................... 14
2.4.2 Hypoxie beeldvorming ......................................................................................................................... 14
2.4.3 Proliferatie beeldvorming: [18F]FLT .................................................................................................... 15
2.5 RF voor beeldvorming in de neurologie ................................................................................................... 15
2.5.1 Beeldvorming van het dopaminesysteem ........................................................................................... 15
2.5.2 Beeldvorming van het serotoninesysteem .......................................................................................... 16
2.5.3 Beeldvorming van de GABA-receptor .................................................................................................. 16
2.5.4 Beeldvorming in de ziekte van Alzheimer ........................................................................................... 16
, 2.5.5 Brain perfusie ...................................................................................................................................... 17
3.1 Introductie ............................................................................................................................................... 18
3.2 Basisprincipes........................................................................................................................................... 18
3.2.1 PET vs SPECT tracers ............................................................................................................................ 18
3.2.2 SPECT ................................................................................................................................................... 19
3.2.3 PET ....................................................................................................................................................... 19
3.3 Diagnose en staging ................................................................................................................................. 20
3.3.1 Diagnose .............................................................................................................................................. 20
3.3.2 Kanker staging (TNM staging) .............................................................................................................. 20
3.4 Voorbij FDG in lage of non-FDG gevoelige tumoren ................................................................................ 21
3.4.1 Somatostatine receptor beeldvorming ............................................................................................... 21
3.4.2 PSMA-PET ............................................................................................................................................ 22
3.4.3 FET en FAPi-PET ................................................................................................................................... 22
3.5 Detectie van recidief ................................................................................................................................ 22
3.6 Therapie respons evaluatie ...................................................................................................................... 23
3.7 Personalized Medicine ............................................................................................................................. 24
3.8 Radionucleïde therapie: theranostics ...................................................................................................... 25
4.1 Introduction ............................................................................................................................................. 26
4.1.1 Evidence based medicine .................................................................................................................... 26
4.1.2 Nadelen in vitro modellen ................................................................................................................... 26
4.1.3 In vivo modellen .................................................................................................................................. 27
4.2 Overview: in vivo cancer models ............................................................................................................. 27
4.2.1 Syngeneïsche modellen ....................................................................................................................... 27
4.2.2 Xenogeneïsche modellen..................................................................................................................... 28
4.2.3 Immunodeficiënte muismodellen ....................................................................................................... 29
4.2.4 Locatie van inoculatie/implantatie ...................................................................................................... 29
4.2.4.1 Subcutane kankermodellen ........................................................................................................ 29
4.2.4.2 Orthotope kankermodellen ........................................................................................................ 30
4.2.4.3 Andere in vivo kankermodellen .................................................................................................. 30
4.2.5 Rat models in cancer research ............................................................................................................. 30
4.2.5.1 De athymische naakte rat ........................................................................................................... 30
4.2.5.2 Voordelen van rat modellen ....................................................................................................... 31
4.3 Molecular Imaging Modalities ................................................................................................................. 32
4.3.1 Bioluminescene (BLI) ........................................................................................................................... 33
4.3.2 Fluorescence molecular imaging (FMT) ............................................................................................... 34
4.3.3 Positron emmision tomography (PET) ................................................................................................. 34
4.4 Preclinical cancer models for PET imaging ............................................................................................... 35
, 4.4.1 Tumor metabolisme (18F-FDG)............................................................................................................. 35
4.4.1.1 Vasten – opwarmen .................................................................................................................... 36
4.4.1.2 FDG injectie ................................................................................................................................. 36
4.4.1.3 Anesthesie................................................................................................................................... 36
4.4.1.4 Bloed glucose levels .................................................................................................................... 37
4.4.2 Tumor proliferatie (18F-FLT) ................................................................................................................. 37
4.4.3 Tumor apoptose (99mTc-Annexin A5, 18F-CP18,…) ................................................................................ 38
4.4.4 Tumor hypoxia (18F-FMISO, 18F-HX4) ................................................................................................... 39
5.1 Introductie ............................................................................................................................................... 42
5.2 SPECT instrumentatie ............................................................................................................................... 43
5.2.1 Collimators ........................................................................................................................................... 43
5.2.1.1 Parallel beam collimatie.............................................................................................................. 44
5.2.1.2 Converging beam collimator ....................................................................................................... 45
5.2.1.3 Pinhole imaging........................................................................................................................... 45
5.2.2 Detectors ............................................................................................................................................. 46
5.2.2.1 Scintillatie detectie ..................................................................................................................... 46
5.2.2.2 Anger logica ................................................................................................................................ 47
5.2.2.3 Photon multiplier tube (PMT) ..................................................................................................... 48
5.3 Image degradation ................................................................................................................................... 48
5.3.1 Attenuatie en verstrooiing................................................................................................................... 48
6.1 PET techniek – overview .......................................................................................................................... 50
6.2 Time of flight (TOF) PET ........................................................................................................................... 50
6.3 PET in nucleaire beeldvorming ................................................................................................................ 51
6.4 Positron Emission Tomography principe ................................................................................................. 51
6.5 PET in de praktijk ..................................................................................................................................... 51
6.5.1 PET gebruik .......................................................................................................................................... 51
6.5.2 Isotoop productie ................................................................................................................................ 52
6.6 Technische aspecten van PET scanners ................................................................................................... 52
7.1 Statische PET beeldvorming ..................................................................................................................... 55
7.2 SUV kwantificatie ..................................................................................................................................... 56
7.2.1 Activiteitsconcentratie......................................................................................................................... 56
7.2.2 SUV kwantificatie ................................................................................................................................. 56
7.2.3 Opmerkingen bij de SUV-berekening .................................................................................................. 57
7.2.4 Statische kwantificatie ......................................................................................................................... 57
7.2.5 SUV tumor ........................................................................................................................................... 57
7.2.6 Statische beeldvorming ....................................................................................................................... 58
7.3 Dynamische PET beeldvorming ................................................................................................................ 59
, 7.4 Farmacokinetische modellering ............................................................................................................... 60
7.4.1 Wat is farmacokinetische modellering ................................................................................................ 60
7.4.2 Compartimentenmodel ....................................................................................................................... 60
7.4.3 Input functie ........................................................................................................................................ 62
7.4.4 One tissue compartmental model (1TCM) .......................................................................................... 62
7.4.5 Two tissue compartmental model ....................................................................................................... 64
7.4.6 Micro & macro -parameters ................................................................................................................ 65
7.5 Zelftest ..................................................................................................................................................... 65
BEELDVORMING
INHOUDSOPGAVE
1.1 Wat is nucleaire biomedische beeldvorming? ........................................................................................... 5
1.2 SPECT (single photon emission computerized tomography) ..................................................................... 5
1.2.1 Humaan SPECT....................................................................................................................................... 5
1.2.1.1 Nucleaire aspect ........................................................................................................................... 5
1.2.2 Small animal SPECT ................................................................................................................................ 6
1.3 PET (positron emissie tomografie) ............................................................................................................. 6
1.3.1 Humaan PET........................................................................................................................................... 6
1.3.2 Small animal PET .................................................................................................................................... 7
2.1 Radiofarmaceutica ..................................................................................................................................... 8
2.2 Ontwikkeling van radiofarmaceutica ......................................................................................................... 8
2.2.1 Bepaling van het target ......................................................................................................................... 8
2.2.2 Vehicle, vector or targeting molecule ................................................................................................... 9
2.2.3 Keuze van radio-isotoop ........................................................................................................................ 9
2.2.3.1 Radiofarmaceutica voor diagnose ................................................................................................ 9
2.2.3.2 Radiofarmaceutica voor therapie ............................................................................................... 10
2.2.3.3 Beschikbaarheid van het radio-isotoop ...................................................................................... 10
2.2.4 Radiolabeling en optimalisatie van radiolabeling ................................................................................ 11
2.2.5 Zuivering van precursor en ongebonden radiolabel ............................................................................ 12
2.2.6 Steriele formulering en quality control van RF .................................................................................... 12
2.2.7 In vitro evaluatie .................................................................................................................................. 13
2.2.8 In vivo evaluatie ................................................................................................................................... 13
2.3 Vereisten voor radiofarmaca ................................................................................................................... 13
2.4 RF voor beeldvorming in de oncologie .................................................................................................... 14
2.4.1 Glucose metabolisme: 18F-fluorodeoxyglucose ................................................................................... 14
2.4.2 Hypoxie beeldvorming ......................................................................................................................... 14
2.4.3 Proliferatie beeldvorming: [18F]FLT .................................................................................................... 15
2.5 RF voor beeldvorming in de neurologie ................................................................................................... 15
2.5.1 Beeldvorming van het dopaminesysteem ........................................................................................... 15
2.5.2 Beeldvorming van het serotoninesysteem .......................................................................................... 16
2.5.3 Beeldvorming van de GABA-receptor .................................................................................................. 16
2.5.4 Beeldvorming in de ziekte van Alzheimer ........................................................................................... 16
, 2.5.5 Brain perfusie ...................................................................................................................................... 17
3.1 Introductie ............................................................................................................................................... 18
3.2 Basisprincipes........................................................................................................................................... 18
3.2.1 PET vs SPECT tracers ............................................................................................................................ 18
3.2.2 SPECT ................................................................................................................................................... 19
3.2.3 PET ....................................................................................................................................................... 19
3.3 Diagnose en staging ................................................................................................................................. 20
3.3.1 Diagnose .............................................................................................................................................. 20
3.3.2 Kanker staging (TNM staging) .............................................................................................................. 20
3.4 Voorbij FDG in lage of non-FDG gevoelige tumoren ................................................................................ 21
3.4.1 Somatostatine receptor beeldvorming ............................................................................................... 21
3.4.2 PSMA-PET ............................................................................................................................................ 22
3.4.3 FET en FAPi-PET ................................................................................................................................... 22
3.5 Detectie van recidief ................................................................................................................................ 22
3.6 Therapie respons evaluatie ...................................................................................................................... 23
3.7 Personalized Medicine ............................................................................................................................. 24
3.8 Radionucleïde therapie: theranostics ...................................................................................................... 25
4.1 Introduction ............................................................................................................................................. 26
4.1.1 Evidence based medicine .................................................................................................................... 26
4.1.2 Nadelen in vitro modellen ................................................................................................................... 26
4.1.3 In vivo modellen .................................................................................................................................. 27
4.2 Overview: in vivo cancer models ............................................................................................................. 27
4.2.1 Syngeneïsche modellen ....................................................................................................................... 27
4.2.2 Xenogeneïsche modellen..................................................................................................................... 28
4.2.3 Immunodeficiënte muismodellen ....................................................................................................... 29
4.2.4 Locatie van inoculatie/implantatie ...................................................................................................... 29
4.2.4.1 Subcutane kankermodellen ........................................................................................................ 29
4.2.4.2 Orthotope kankermodellen ........................................................................................................ 30
4.2.4.3 Andere in vivo kankermodellen .................................................................................................. 30
4.2.5 Rat models in cancer research ............................................................................................................. 30
4.2.5.1 De athymische naakte rat ........................................................................................................... 30
4.2.5.2 Voordelen van rat modellen ....................................................................................................... 31
4.3 Molecular Imaging Modalities ................................................................................................................. 32
4.3.1 Bioluminescene (BLI) ........................................................................................................................... 33
4.3.2 Fluorescence molecular imaging (FMT) ............................................................................................... 34
4.3.3 Positron emmision tomography (PET) ................................................................................................. 34
4.4 Preclinical cancer models for PET imaging ............................................................................................... 35
, 4.4.1 Tumor metabolisme (18F-FDG)............................................................................................................. 35
4.4.1.1 Vasten – opwarmen .................................................................................................................... 36
4.4.1.2 FDG injectie ................................................................................................................................. 36
4.4.1.3 Anesthesie................................................................................................................................... 36
4.4.1.4 Bloed glucose levels .................................................................................................................... 37
4.4.2 Tumor proliferatie (18F-FLT) ................................................................................................................. 37
4.4.3 Tumor apoptose (99mTc-Annexin A5, 18F-CP18,…) ................................................................................ 38
4.4.4 Tumor hypoxia (18F-FMISO, 18F-HX4) ................................................................................................... 39
5.1 Introductie ............................................................................................................................................... 42
5.2 SPECT instrumentatie ............................................................................................................................... 43
5.2.1 Collimators ........................................................................................................................................... 43
5.2.1.1 Parallel beam collimatie.............................................................................................................. 44
5.2.1.2 Converging beam collimator ....................................................................................................... 45
5.2.1.3 Pinhole imaging........................................................................................................................... 45
5.2.2 Detectors ............................................................................................................................................. 46
5.2.2.1 Scintillatie detectie ..................................................................................................................... 46
5.2.2.2 Anger logica ................................................................................................................................ 47
5.2.2.3 Photon multiplier tube (PMT) ..................................................................................................... 48
5.3 Image degradation ................................................................................................................................... 48
5.3.1 Attenuatie en verstrooiing................................................................................................................... 48
6.1 PET techniek – overview .......................................................................................................................... 50
6.2 Time of flight (TOF) PET ........................................................................................................................... 50
6.3 PET in nucleaire beeldvorming ................................................................................................................ 51
6.4 Positron Emission Tomography principe ................................................................................................. 51
6.5 PET in de praktijk ..................................................................................................................................... 51
6.5.1 PET gebruik .......................................................................................................................................... 51
6.5.2 Isotoop productie ................................................................................................................................ 52
6.6 Technische aspecten van PET scanners ................................................................................................... 52
7.1 Statische PET beeldvorming ..................................................................................................................... 55
7.2 SUV kwantificatie ..................................................................................................................................... 56
7.2.1 Activiteitsconcentratie......................................................................................................................... 56
7.2.2 SUV kwantificatie ................................................................................................................................. 56
7.2.3 Opmerkingen bij de SUV-berekening .................................................................................................. 57
7.2.4 Statische kwantificatie ......................................................................................................................... 57
7.2.5 SUV tumor ........................................................................................................................................... 57
7.2.6 Statische beeldvorming ....................................................................................................................... 58
7.3 Dynamische PET beeldvorming ................................................................................................................ 59
, 7.4 Farmacokinetische modellering ............................................................................................................... 60
7.4.1 Wat is farmacokinetische modellering ................................................................................................ 60
7.4.2 Compartimentenmodel ....................................................................................................................... 60
7.4.3 Input functie ........................................................................................................................................ 62
7.4.4 One tissue compartmental model (1TCM) .......................................................................................... 62
7.4.5 Two tissue compartmental model ....................................................................................................... 64
7.4.6 Micro & macro -parameters ................................................................................................................ 65
7.5 Zelftest ..................................................................................................................................................... 65
