Van Gen tot Geneesmiddel: Nuclear Imaging techniques
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1 uclear Medicine & PET Research Van Gen tot Geneesmiddel: uclear Imaging techniques Part 4. PET in the Clinic Bert Windhorst Radiopharmaceutical scientist VU University Medical Center Amsterdam 1
2 uclear Medicine & PET Research Outline 2 cases: [ 89 Zr]trastuzumab (herceptin) 11 C]PIB [ 11 2
3 uclear Medicine & PET Research HER2 and breast cancer HER2 amplification/overexpression overexpression correlates with worse prognosis Trastuzumab: : anti-her2 monoclonal IgG1 antibody for treatment of HER2 positive breast cancer 3
4 Rationale for imaging HER2 in breast cancer uclear Medicine & PET Research on-invasive measurement of HER2 receptor status 4
5 uclear Medicine & PET Research 111 In-DTPA DTPA-trastuzumab SPECT/CT ewly discovered tumor lesions in 13/15 patients 5
6 Optimization of HER2 imaging uclear Medicine & PET Research Use PET to: Improve spatial resolution Increase signal-to to-noise ratio Development of PET tracer: Zirconium-89 ( 89 Zr) Long-living isotope (T ½ = 78 hr) Suitable for clinical use 6
7 Trastuzumab radiolabeling uclear Medicine & PET Research Desferal 89 Zr-labeled MAb 89 Zr-trastuzumab is obtained in 6 simple steps 7
8 89 Zr uclear Medicine & PET Research Characteristics of 89 Zr-trastuzumab Excellent radiochemical purity (>95%) High specific activity (>50 MBq/mg) Maintenance of antigen binding (>80%) Long-term stability in 37 C C human serum 8
9 uclear Medicine & PET Research Animal study design Athymic mice with HER2 positive or negative xenograft 5 MBq 89 Zr-trastuzumab iv At 1, 3 & 6 days: micropet imaging & biodistribution 9
10 89 Zr-trastuzumab tumor uptake uclear Medicine & PET Research Day 1 Day 6 Macroscopic metastases IHC confirmed HER2 expression 10
11 89 Zr uclear Medicine & PET Research Zr-trastuzumab specific tumor uptake in mice 11
12 uclear Medicine & PET Research Design clinical HER2 imaging study Aim Visualize HER2 positive tumors Find minimal trastuzumab dose required for optimal imaging Eligible patients Metastatic HER2 positive breast cancer (n=8) Imaging procedure 37 MBq 89 Zr-trastuzumab ( ( 20 msv) ) and PET scans days 1-51 Compare to available CT, MRI and bone scans 12
13 uclear Medicine & PET Research Tumor visualization Day 4 13
14 uclear Medicine & PET Research Metastasis in the brain 14
15 uclear Medicine & PET Research Conclusion [ 89 Zr]trastuzumab imaging is developed as a non invasive imaging technique to determine HER2 receptors in vivo ext: larger trial in patients to validate diagnostic value 89 Zr labelling applicable to any MAb. 15
16 uclear Medicine & PET Research Further reading Immuno-PET: A avigator in Monoclonal Antibody Development and Applications By Guus van Dongen et al (Blackboard) 16
17 uclear Medicine & PET Research Alzheimer s s disease [ 11 C]PIB imaging, from research tool to clinical practice 17
18 uclear Medicine & PET Research AD at the cellular level Senile plaques Cause of degeneration Post-mortem 18
19 Biological targets to image uclear Medicine & PET Research Amyloid-β (Aβ) eurofibrillary tangles (FTs( FTs) 19
20 uclear Medicine & PET Research Several leads explored 125 I Aβ peptides Early 90 s, in vivo: rapid metabolism, low brain uptake (Maggio et al, PAS, 1992;89:5462) 99m Tc Tc labelled antibodies (mouse and Fab) Human trial: no specific signal Friedland et al, Ann Y Acad Sci,, 1997;826:242 Bickel et al, Bioconjug Chem,, 1994;5:119 20
21 Staining compounds as leads uclear Medicine & PET Research A few of compounds In vitro assays, hydrophilic compounds Lead optimization via Affinity Lipophilicity 21
22 uclear Medicine & PET Research First lead: Congo Red H 2 H 2 congo red Kd 1100 nm LogD ao 3 S HOOC HO SO 3 a COOH OH chrysamine-g Kd 350 nm LogD HOOC COOH X-34 Ki 452 nm LogD MeO HO OH MeO-X-04 Ki : 27 nm LogD 7.4 :
23 Second lead: Thioflavin-S uclear Medicine & PET Research Major compound: Thioflavin-T + S Ki : 890 nm LogD 7.4 :
24 Development of [ 11 C]PIB uclear Medicine & PET Research R1 S R2 R3 R1: OH, MeO, fluoroalkyl ether R2/R3: Me, fluoroalkyl 24
25 Development of [ 11 C]PIB uclear Medicine & PET Research HO S H CH 3 -methyl-2-(4 methylaminophenyl) methylaminophenyl)-6-hydroxybenzothiazolehydroxybenzothiazole 6-OH-BTA-1, PIB Ki 4 nm LogD
26 [ 11 C]PIB labeling uclear Medicine & PET Research [ 11 THF HI C]CO 2 + LiAlH 4 [ 11 C]CH 3 OLi [ 11 C]CH 3 I 1 min, RT 1 min, 130 o C H i 2 O O S O O S H 11 CH3 ii i) [ C]CH 3 I, 130 ºC, 5 min ii) MeOH/HCl,, 80ºC, 3min ; 60% HO S [ 11 C]PIB H 11 CH3 Yield: MBq EOS (10% cfd) SA: GBq/µmol > 40, fail rate>15% 26
27 [ 11 C]PIB labeling uclear Medicine & PET Research [ 11 C]CH 3 I + CF 3 OSO 2 Ag GraphPac 200 o C, on-line CF 3 OSO 2 [ 11 C]CH 3 HO S H 2 MEK 80 o C, 1 min HO S H 11 CH3 [ 11 C]PIB 27
28 uclear Medicine & PET Research Control vs AD patient control patient
29 uclear Medicine & PET Research Disease progress 29
30 uclear Medicine & PET Research Conclusion Amyloid plaques imaging with [ 11 C]PIB works good ew tool in standard diagnosis Used in clinical research as well 30
31 uclear Medicine & PET Research Further reading Amyloid imaging in Alzheimer s s disease: a promising new direction in uclear Medicine By Bart van Berckel (on blackboard) 31
32 uclear Medicine & PET Research The Gene-to to-medicine paradigm Target discovery Chem diversity Hit optimise safety efficacy genomics Lead chem HTS SAR Pre clinical human bio informatics chemo informatics imaging 32
33 uclear Medicine & PET Research Final remarks Imaging of biological targets is feasible Molecular Imaging is a valueble tool Especially in translational research. It is the bridge between bench and bedsie, between lab and clinic ext years more indepth classes. 33
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