PET Primena

Production, Use and Applications of 124I
Jason S. Lewis, PhD

Chief, Radiochemistry Service Director, Cyclotron-Radiochemistry Core Memorial-Sloan Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center
No Financial Disclosures
Presentation Decay Schemes, Cross Sections Solid Targetry, Production, Separation Methods Clinical Applications
124I
Decay Scheme
T = 4.176 d at least 25 electron capture transitions,6 positron transitions and 97 gamma-ray transitions. ~23% of disintegrations result in positron emission while the gamma ray abundance >90% per disintegration.
124I 53
Number of distintegrations
+ +
Maximum energy (MeV) 0.820 1.543 2.146 0.603 0.723 1.325 1.376 1.509 1.691
Average energy (Mev) 0.366 0.686 0.974
0.002 0.113 0.113 0.605 0.100 0.014 0.017 0.030 0.104
124Te 52
(stable)
MIRD Radionuclide Data and Decay Schemes
Image Quality
A mini Derenzo phantom filled with radionuclides imaged on a microPET- Focus scanner (Siemens Medical Systems). It is important to note that although this degradation is noted with small animal PET scanners with high resolution (1- 2 mm), this degradation is often not seen with clinical scanners with 4-5 mm resolution. New reconstruction algorithms can also be used to enhance image quality. Images are courtesy of Dr. Richard Laforest, Washington University School of Medicine
Routes for Production of 124I

(values calculated from excitation functions measured at Jlich, Courtesy of Dr. Syed Qaim) Nuclear reaction Energy range [MeV] Thick target yield of 124I [MBq/Ah] (mCi/Ah) 17.5 (0.47) 16 (0.43) 81 (2.19) 222 (6) 1.02 (0.03) 2.1(0.06) 0.95 (0.03) Impurity [%]
123I 125I 126I
(13.3 h) 1.0 7.4 148 890 895 3877
(59.4 d) 1.7 < 0.1 0.9 1.0 13 <0.2 0.6
(12.9 d) 1.0 16 <0.2 0.6
124Te(d,2n) 124Te(p,n) 125Te(p,2n) 126Te(p,3n) natSb(,xn) 121Sb(,n) natSb(3He,xn)
14 10 12 8 21 15 38 28 22 13 22 13 35 13
124Te(p,n)
reaction gives the purest form of 124I
Targetry - MSKCC
Washington University
Dry distillation under Argon atmosphere
Washington University 76Br Can remove up to 90% of the radioactivity from the 63Cu276Se target. Activity is trapped on quartz tube. Removal of radioactivity by washing with NH4OH. Recovery of radioactivity up to 76%.
Washington University 76Br

2.000 1.800 1.600 Production Rate (mCi/uA*h) 1.400 1.200 1.000 0.800 0.600 0.400 0.200 0.000 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 Run
Quartz tube changed every two or three productions
120.0%
100.0%
Percent Recovered
80.0%
60.0%
40.0%
20.0%
0.0% 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 Run
University of Wisconsin: Vertical Target Station
Passive Armco Singlet

(L.R. Carroll et al., Int Symp Radiopharm Chem, Sydney, Australia, 2003)
Quad Slit Set
CTI RDS 112 11MeV
Vertical Solid Target w/KF Mounting Chilled He Cooling Rig at 3 Liter/sec
Courtesy of R. Jerry Nickles, PhD J. A. Nye UW PhD Thesis
University of Wisconsin: Sloping Solid Target

Irradiation Conditions
20-degree incline 20 mil Platinum foil crucible 200 mg Al2Te3 11 2.5 MeV 3L/sec circulating chilled helium 30% Power in helium stream
dry ice
University of Wisconsin: Harvesting Iodine

Thermal distillation of iodide from Al2124Te3 glassy melt 900o C, sublimation of iodide in air stream Trapped on chilled capillary quartz tube loaded w/Pt wire on a film of weak base
24/40 grindings
Carbolite Furnace
15 SCCM Air
Charcoal trap
Dry ice
Exhaust Courtesy of R. Jerry Nickles, PhD J. A. Nye UW PhD Thesis
Targetry - Hammersmith Imanet

"Spoon" Furnace
Helium Water
Furnace tube
O2
Protons 12.5 MeV
Al2O3
Charcoal NaOH (20 mM)
Target holder Cover foil Target
Relative target yield, decay-corrected (MBq/Ah)
800 700 Furnace temperature ( C) 600 500 400 300 200 100 0 0 5 10 15 20 25 30 35 Time (min)
Furnace temperature Detector response
o
12
Relative Target yield Batch yield
400 350 300 Batch yield (MBq)
Relative target yield, decay-corrected (MBq/Ah)
5000 4000 3000 2000 1000 0 Detector response (cpm)
200
10 8 6 4 2 0 10 20 Run No. 30 40
150
250 200 150 100 50 0
100
50
0 0 5 10 15 20 25 30 35 40
Integrated beam current (Ah)
Courtesy of Mathias Glaser, PhD
State University of New York, Buffalo
Courtesy of Erol Bars, PhD
State University of New York, Buffalo
I-124 Production
Overview
Nuclear reaction: 124Te (p,n) 124I Route selected for both high yield and high purity 124Te enriched Tellurium Oxide (TeO ) is the target material 2 material Thermo-distillation selected as recovery process Recovery method associated with high recovery yields (90%) (90%) High Specific Activity (No Carrier Added) is desired High radioactive concentration [124I]NaI in NaOH solution (pH of 8.5) prevents volatilization volatilization Flexibility to trap 124I in other solutions, and perform direct Data prepared by direct Bob Ylimaki, Bernard Lambert, Jean-Michel Geets radio-labeling of precursors
2006
I-124 Production
IBA nirta solid target Optimized for 124TeO2 Low thermal conductivity He cooling protects target matrix Remotely unloaded
2006
IBA Nirta Solid target
Target disk 24mm
2006
I-124 Production
Process
Target Disk Irradiation

Optimal energy range for 124I production production while minimizing co-produced 123I: produced 123I: 14 - 9 MeV Niobium degrader foil installed in target target Thick target (0.9mm) fully stops beam 25A at 13Mev Typical irradiation: 10-12 hours
2006
I-124 Production
124I
Typical Production Yields
100 90 80 70 60 mCi 50 40 30 20 10 0 0 50 100 uA-h 150 200 250
Target Yield
Production Yield
124Te
enrichment of 99.86%
Optimal 9-13 MeV makes less less (< 3% vs. 30%) 123I impurity, conserving 124Te; As built: 100 mCi per 8 hour hour production @ 25 A (single) Dual beam possible
Agreement with predicted 20MBq (0.54mCi)/uAh
2006
I-124 Production
124I
Process
Radioiodine Recovery
Thermo-chromatographic recovery associated with high yield yield Diffusion/transport/trapping regimes optimized for iodide oxidation oxidation species and target regeneration Minimal maintenance Nominal 90-95% trapping yield in 0.02M NaOH (less than 500 l) 500 l)
2006
I-124 Production
124I
Quality Control
Radionuclidic Purity
Hyper-pure Germanium (HPGe) gamma spectrometry Conformance with American National Standards Institute (ANSI) Institute (ANSI) Standard N42.14 assures universal acceptance acceptance Traceable 152Eu standard used for daily calibration
123I
impurity minimized at End of Separation (EOS)
impurity levels below detection threshold of 0.1% threshold of 0.1% Te content : less than 1g/ml
125I, 126I, 130I, 131I
2006
I-124 Radiolabeled compounds

I-124, NaI solution, activity level up to 20 mCi I-124 MIBG Collaboration : Wilex compound I-124 Radiolabeled cG250 antibody Renal cell carcinoma imaging Estimated worldwide 480,000 uncharacterized uncharacterized renal masses are annually identified Prevents unnecessary nephrectomies I-124 ?? Other compounds
2006
124I
IBA production centers
VU, Amsterdam
IBA VCU, Richmond
2006
IBA Radioisotopes - Belgium

Fleurus facility: (14MeV- 1mA)
R&D center and radioisotopes production center
2006
GEMS NIH and Tubingen
ACOM (Italy)
ACOM (Italy)
ACOM (Italy)
124I
Production Summary
Energy (MeV) 15.4 12.5 13.0 12.5 15.0 14.7 12.5 14.0 11.0 16.0 14.1 0.23 0.16 0.53 0.64 (90% theor.) Experimental Yield (mCi/Ah) 0.49 - 0.52 (n=10) 60 - 64% theor. 0.26 0.02 (n = 47) 0.5 (93% theor.) 0.018 0.005 (n = 4) 0.15 0.02 (n = 24) 0.54 0.26 0.02 15 A/2h 18 A/4h 10 A/8h 24 A/8h 12.0 12.7 ~110.0 25 A/68h 15 - 25 ~30 Typical run 12 A/8h 10 A/2h 25 A/8h Actual activity (mCi) 50.9 - 56.8 5.48 100.0
Center ACOM Hammersmith IBA NIH Tbingen MSKCC WUSTL Essen Wisconsin Jlich Buffalo
ACOM, IBA 18 MeV IBA cyclotron using COSTIS; Buffalo 30 MeV IBA cyclotron; NIH, Tbingen GE PETtrace; MSKCC EBCO TR19; WUSTL CS15; Wisconsin CTI 11 MeV; Essen CS28; Hammersmith Scanditronix MC40
Target Substrates and Yields

Center Target (mg) 260 1100 600 200 TeO2 TeO2 Cu2Te TeO2 200 200 600 TeO2 Al2Te3 TeO2 TeO2 TeO2 Substrate Enrichment Al2O3 w/w (%) 5 0.746 6 6.7 5 >30 70 5% 31% 80% 6 5 5.2 89 5% 65% 95% 90% 90% Specific Activity (Ci/mol) Isolation Yield
ACOM Hammersmith IBA Tbingen MSKCC WUSTL Essen Wisconsin Jlich Buffalo
99.50 99.3 99.86 99.8 99.8 99.7 96.0 99.5 99.8 99.86
Clinical Applications
Na124I has been used for the diagnosis of thyroid disease and for evaluating the spread of metastatic thyroid carcinoma. (Eschmann et al., Eur J
Nucl Med Mol Imaging. 2002;29:760-67; Freudenberg et al., Eur Radiology 2003;13:L19-L23)
One study reported the distribution of 124I in 64 patients with a variety of thyroid conditions (Frey P,
et l., J Clin Endocrin Metab. 1986;63:918-27)
A number of small molecules have been labeled with 124I as analogs of 131I compounds; e.g., 131/124I-mIBG. (Ott RJ, et al.,Br J Radiol. 1992;65:787-91)
is a specific marker substrate for gene expression of HSV-1-tk. Used to identify the location, magnitude, and extent of vectormediated HSV-1-tk gene expression in a phase I/II clinical trial of gene therapy for recurrent glioblastoma in five patients. (Jacobs A, et al., Lancet
Oncology. 2001;358:729-29)
124I-FIAU
has been used to measure the proliferative activity of tumors in 20 patients with brain tumors, including meningiomas and gliomas. (Blasberg RG, et al. Cancer Research. 2000;60:624-35)
124I-IUdR
[124I]FIAU signal in established infections as imaged by PET/CT: Fused PET and CT images, taken at 2 hours after radiotracer administration.
124I-Dosimetry
in Metastases
PK, 53 yo white male with numerous pulmonary nodules discovered on routine CXR, while being W/U for prostate Ca 4/28/00 Papillary thyroid Ca, moderately differentiated, locally invasive, 2.0 cm in diameter, with 13/23 lymph nodes Refered for Dosimetry 7/2000
124I
Thyroid Imaging
CXR PA . 4/25/2000
LT.
124I-Iodine
in Thyroid Cancer
203 cGy/mCi 229 cGy/mCi
125 cGy/mCi
277269
Differentiation and Oncofetal Antigens
G250- Carbonic anhydrase IX, a chronic hypoxia response protein

PET provides excellent imaging with 124I-cG250 in clear cell cancer
Determination of carbonic anhydrase IX expressing phenotype, identifies clear cell and determines surgical approach Divgi et al: Lancet Oncol. 2007 Apr;8(4):304-10.
124I-cG250
(5 mCi, 10 mg)
6D
Fusion
Non Contrast (PET/CT
Contrast CT
A33 antigen: a tight junction protein

Not constitutively internalized Accumulation in junctional complex components Possibly suitable for multistep targeting methods
A33-occludin
Courtesy I Mellman, PhD
015:LD
70 YO Female Presented with anemia. Splenic flexure lesions, hepatic metastasis. 2/6/07 2 foci Adenocarcinoma with mucinous feature <50%, moderately differentiated splenic 5.5 x 5.1 x2 cm and cecum 3.5 x3 x2 cm Liver metastasis #3 largest 3.1 cm 9/12/07 NED on chemo
in Colorectal Ca: uptake in occult aorto-caval node
124I-A33
I-124 A33
FDG
CT
Fused A33-CT
124I-A33
in Primary Colorectal Cancer
010:RK
65 yo presented with rectal cancer stage IV to the liver at presentation 9/5/02 Initial surgery 5/29/03 rectum and liver Recurrent liver metastasis 11/22/2005 Liver Metastatic adenocarcinoma consistent with colorectal 4.1 cm. and concurrent : Metastatic disease to lymph node
010:RK
FDG
I-124 A33 7 D
FUSION
Correlation of antigen sites with antibody uptake

0.018 0.016 0.014 Tumor 0.012 0.010 0.008 0.006 0.004 0.002 0.000 0 2 4 6 Mid Colon LN Colon
Data: Data33_B M odel: linear Chi^2 R^2 a b = 2.7481E-6 = 0.88546 0.00244 0.00202 0.00088 0.00027
Correlation Between I-A33 In Vivo Uptake and In Vitro Determination of A33 sites
Ileum
124
124
I-A33 (% ID/g)
Sites (pm oles/mg)
Images of 124I-A33 (IVIG) in Patient No.13

Tumor tissue-1 (Aorta lymph node) Tumor tissue-2 (Anterior aortic node) Tumor tissue-3 (Vena lymph node)
ARG (72h expo)
Section T1S2-10, 6x12mm
Section T2S10, 8x11mm
H&E
Section T1S2-10, 6x12mm Section T2S10, 8x11mm
MSKCC Novel Antibodies A33: Colorectal Cancer G250: Renal Cancer F-19: Colorectal; Breast; Pancreatic 3F8: Neuroblastoma; SCLC; Glioma; Melanoma; Sarcoma M195: AML, PML, CML
3F8* Anti-GD2 Neuroblastoma SCLC Brain tumors Osteosarcoma
Drs. NKV Cheung, B. Kushner, K. Kramer, Shakeel Modak
CNS Neuroblastoma Dosimetry and Treatment with radiolabeled 3F8 antibody

Ludwig Center for Cancer Immunotherapy Pediatric PO1 Cheung and Kramer
Sagittal section from serial 124I-3F8 PET images of pediatric patient with neuroblastoma
4 hours 24 hours 48 hours
Quantitative PET images used to estimate the radiation dose from 50 mCi of 131I-3F8. CSF in 4th ventricle = 2,176 cGy thoracic CSF = 1,004 cGy
Patient #1:
Patient #2:
Salvage
Regimen
Salvage
Regimen
PFS at 5 yrs
PFS at 4 yrs
Long standing CR after clearance of CSF and MR
1 month post 30 mCi 131I-8H9
New Directions Small Molecules
Radiolabeled Small Molecule Inhibitor of HSP 90 - [124I]PU-DZ8

N H N O
124I
N N
H2 N
2-fluoro-9-[3-2-propylamino)propyl]-8(4-iodo-1,3-benzodioxol-5-yl)methyl adenine
PI: Gabriela Chiosis, PhD with Kishore Pillarsetty, Ph.D.
Ansamycins bind to the ADP\ATP switch site in Hsp90

O H3CO O Me N H O O NH2 OMe
O Me OH MeO
Me Me
Geldanamycin (GM)
O O Me N H O O NH2 OMe
H N
O Me OH MeO
Me Me
17-AAG
124I-PU-DZ8
in Breast Cancer
3 hours
17 hours
Acknowledgements
Howard Sheh and the Cyclotron Team - MSKCC Drs. Steven Larson and Jorge Carrasquillo MSKCC Dr. Gabriela Chiosis - SKI Drs. Peter Smith-Jones and Kishore Pillarsetty - MSKCC Dr. Syed Qaim Forschungszentrum Jlich Dr. Paola Panichelli ACOM Spa, Italy Dr. Jerry Nickels University of Wisconsin Dr. Mathias Glaser Hammersmith Imanet Ltd Drs. Bob Ylimaki, Bernard Lambert, Jean-Michel Geets IBA Dr. Erol Bars State University of New York, Buffalo Lucie Tang Washington University Drs. Uno Zetterbery, Erik Stromqvist, Armando Sera - GEMS

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Production, Use and Applications of 124I

Jason S. Lewis, PhD

Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center

Average energy (Mev) 0.366 0.686 0.974

0.002 0.113 0.113 0.605 0.100 0.014 0.017 0.030 0.104

MIRD Radionuclide Data and Decay Schemes

Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center

Routes for Production of 124I

(13.3 h) 1.0 7.4 148 890 895 3877

(59.4 d) 1.7 < 0.1 0.9 1.0 13 <0.2 0.6

(12.9 d) 1.0 16 <0.2 0.6

124Te(d,2n) 124Te(p,n) 125Te(p,2n) 126Te(p,3n) natSb(,xn) 121Sb(,n) natSb(3He,xn)

reaction gives the purest form of 124I

Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center

Washington University 76Br

Quartz tube changed every two or three productions

Memorial Sloan-Kettering Cancer Center

University of Wisconsin: Vertical Target Station

Passive Armco Singlet

Quad Slit Set

CTI RDS 112 11MeV

Vertical Solid Target w/KF Mounting Chilled He Cooling Rig at 3 Liter/sec

Courtesy of R. Jerry Nickles, PhD J. A. Nye UW PhD Thesis

Memorial Sloan-Kettering Cancer Center

University of Wisconsin: Sloping Solid Target

Memorial Sloan-Kettering Cancer Center

University of Wisconsin: Harvesting Iodine

Exhaust Courtesy of R. Jerry Nickles, PhD J. A. Nye UW PhD Thesis

Memorial Sloan-Kettering Cancer Center

Targetry - Hammersmith Imanet

Charcoal NaOH (20 mM)

Target holder Cover foil Target

Relative target yield, decay-corrected (MBq/Ah)

400 350 300 Batch yield (MBq)

Relative target yield, decay-corrected (MBq/Ah)

5000 4000 3000 2000 1000 0 Detector response (cpm)

250 200 150 100 50 0

Integrated beam current (Ah)

Courtesy of Mathias Glaser, PhD

Memorial Sloan-Kettering Cancer Center

State University of New York, Buffalo

Courtesy of Erol Bars, PhD

Memorial Sloan-Kettering Cancer Center

State University of New York, Buffalo

IBA Nirta Solid target

Target disk 24mm

Target Disk Irradiation

impurity minimized at End of Separation (EOS)

125I, 126I, 130I, 131I

I-124 Radiolabeled compounds

IBA production centers

IBA VCU, Richmond

IBA Radioisotopes - Belgium

R&D center and radioisotopes production center

Memorial Sloan-Kettering Cancer Center

GEMS NIH and Tubingen

Memorial Sloan-Kettering Cancer Center