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Production, Use and

Applications of124I

Jason S. Lewis, PhDChief, Radiochemistry Service

Director, Cyclotron-Radiochemistry Core

Memorial-Sloan Kettering Cancer Center


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Memorial Sloan-Kettering Cancer Center

No Financial Disclosures


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Presentation

Decay Schemes, Cross Sections

Solid Targetry, Production, Separation

Methods

Clinical Applications


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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.

Number of

distintegrations

Maximum

energy (MeV)

Average

energy (Mev)

+

0.002 0.820 0.3660.113 1.543 0.686

0.113 2.146 0.974

0.605 0.603

0.100 0.723

0.014 1.3250.017 1.376

0.030 1.509

0.104 1.691

MIRD Radionuclide Data and Decay Schemes

124I53

124Te (stable)52

+

+

+


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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


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Routes for Production of124I(values calculated from excitation functions measured at Jlich, Courtesy of Dr. Syed Qaim)

Impurity [%]Nuclear

reaction

Energy range

[MeV]

Thick targetyield of 124I

[MBq/Ah](mCi/Ah)

124Te(d,2n) 14 10 17.5 (0.47) - 1.7 -

126Te(p,3n) 38 28 222 (6) 148 1.0 1.0

natSb(,xn) 22 13 1.02 (0.03) 890 13 16

121Sb(,n) 22 13 2.1(0.06) 895


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Targetry - MSKCC


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Washington University

Dry distillation under Argon atmosphere


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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 withNH4OH.

Recovery of radioactivity up to 76%.


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Washington University 76Br

Quartz tube changed

every two or three

productions0.000

0.200

0.400

0.600

0.800

1.000

1.200

1.400

1.600

1.800

2.000

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45

Run

ProductionRate

(mCi/uA*h)

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

120.0%

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45

Run

PercentRecovered


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University of Wisconsin: Vertical Target Station

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

CTI RDS 112 11MeV

Vertical Solid Target w/KF Mounting

Passive Armco Singlet

(L.R. Carroll et al., Int Symp Radiopharm Chem, Sydney,

Australia, 2003)

Quad Slit Set

Chilled He Cooling Rig at 3 Liter/sec


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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

dryice

University of Wisconsin: Sloping Solid Target


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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

Carbolite Furnace24/40grindings

Dry iceCharcoal trap15 SCCM

Air

Exhaust

University of Wisconsin: Harvesting Iodine

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


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Targetry - Hammersmith Imanet

Courtesy of Mathias Glaser, PhD

O2

Al2O

3 Charcoal

NaOH (20 mM)

"Spoon"

Furnace tubeFurnace

Protons12.5 MeV

Helium Water

Cover foilTarget holder

Target

0 10 20 30 40

2

4

6

8

10

12

Relative Target yield

Batch yield

Run No.Re

lativetargetyield,

decay-corrected(MBq/Ah)

0

50

100

150

200

250

300

350

400

Batchyield(MBq)

0 5 10 15 20 25 30 350

100

200

300

400

500

600

700

800

Furnace temperature

Detector response

Time (min)

Furnacetemperature

(oC)

0

1000

2000

3000

4000

5000

Detectorresponse(cpm)

0 5 10 15 20 25 30 35 40

0

50

100

150

200

Relativetargetyield,

decay-corr

ected(MBq/Ah)

Integrated beam current (Ah)


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State University of New York, Buffalo

Courtesy of Erol Bars, PhD

M i l Sl K tt i C C t


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State University of New York, Buffalo


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2006

I-124 Production Overview

Nuclear reaction: 124Te (p,n) 124I

Route selected for both high yield and high purity

124Te enriched Tellurium Oxide (TeO2) is the target materialmaterial

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 volatilizationvolatilization

Flexibility to trap 124I in other solutions, and perform direct

direct

radio-labeling of precursors

Data prepared by

Bob Ylimaki, Bernard Lambert, Jean-Michel Geets


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2006

I-124 Production

IBA nirta solid target

Optimized for

124

TeO2

Low thermal conductivity

He cooling protects

target matrix

Remotely unloaded


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2006

IBA Nirta Solid target

Target disk 24mm


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2006

I-124 Production Process

Target Disk Irradiation

Optimal energy range for124I production

production while minimizing co-produced 123I:produced 123I: 14 - 9 MeV

Niobium degrader foil installed in targettarget

Thick target (0.9mm) fully stops beam

25A at 13Mev

Typical irradiation: 10-12 hours


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2006

I-124 Production Target Yield

Agreement with predicted 20MBq (0.54mCi)/uAh

124I Production YieldTypical Production Y ields

0

10

20

30

40

50

60

70

80

90

100

0 50 100 150 200 250

uA-h

mCi

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

I 124 P d ti P


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2006

I-124 Production Process

124I Radioiodine Recovery

Thermo-chromatographic recovery associated with high yieldyield

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)

I 124 P d ti Q lit C t l


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2006

I-124 Production Quality Control

124I 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)

125I, 126I, 130I, 131I impurity levels below detection threshold of 0.1%threshold of 0.1%

Te content : less than 1g/ml

I 124 R di l b l d d


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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 uncharacterizeduncharacterized renal masses are annually

identified

Prevents unnecessary nephrectomies I-124 ??

Other compounds

124I IBA d ti t


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2006

124I IBA production centers

IBAVCU, Richmond

VU, Amsterdam

IBA Radioisotopes Belgium


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2006

IBA Radioisotopes - Belgium

Fleurus facility: (14MeV- 1mA)

R&D center and radioisotopes production center



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GEMS NIH and Tubingen



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ACOM (Italy)



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ACOM (Italy)



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ACOM (Italy)



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124I Production Summary

Center Energy(MeV)

Experimental Yield(mCi/Ah)

Typicalrun

Actual activity(mCi)

ACOM 15.4 0.49 - 0.52 (n=10)

60 - 64% theor.

12 A/8h 50.9 - 56.8

Hammersmith 12.5 0.26 0.02 (n = 47) 10 A/2h 5.48

Wisconsin 11.0 0.23 18 A/4h 12.0

Jlich 16.0 0.16 10 A/8h 12.7

100.0

15 - 25

WUSTL 12.5 0.26 0.02 ~30

Essen 14.0 15 A/2h

~110.0

IBA 13.0 0.5 (93% theor.) 25 A/8h

NIH 12.5 0.018 0.005 (n = 4)

Tbingen 15.0 0.15 0.02 (n = 24)MSKCC 14.7 0.54 25 A/68h

Buffalo 14.1 0.53 0.64

(90% theor.)

24 A/8h

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



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Target Substrates and Yields

Center Target(mg)

Substrate Enrichment Al2O3 w/w(%)

99.50 5

6

6.7

5

6

5

5.2

99.3

99.86

99.8

99.8

99.7

96.0

99.5

99.8

99.86

IsolationYield

90%

90%

70 5%

31%

80%

65%

95%

89 5%

TeO2

TeO2

TeO2

Cu2Te

TeO2

TeO2

Al2Te3

TeO2

TeO2

SpecificActivity

(Ci/mol)

ACOM 260

Hammersmith 1100 0.746

Wisconsin 200

Jlich 200

IBA

Tbingen 600

MSKCC 200 >30

WUSTL

Essen

Buffalo 600



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Na124I has been used for the diagnosis of thyroid

disease and for evaluating the spread of

metastatic thyroid carcinoma. (Eschmann et al., Eur JNucl Med Mol Imaging. 2002;29:760-67; Freudenberg et al., EurRadiology 2003;13:L19-L23)

One study reported the distribution of124

I in 64patients 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 labeledwith 124I as analogs of131I compounds; e.g.,131/124I-mIBG. (Ott RJ, et al.,Br J Radiol. 1992;65:787-91)



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124I-FIAU is a specific marker substrate for gene

expression of HSV-1-tk. Used to identify the

location, magnitude, and extent of vector-mediated 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., LancetOncology. 2001;358:729-29)

124I-IUdR has been used to measure the

proliferative activity of tumors in 20 patients withbrain tumors, including meningiomas and

gliomas. (Blasberg RG, et al. Cancer Research. 2000;60:624-35)



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[124I]FIAU signal in established infections as imaged by PET/CT: Fused

PET and CT images, taken at 2 hours after radiotracer administration.



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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 indiameter, with 13/23 lymph nodes

Refered for Dosimetry 7/2000


124I Th id I i


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124I Thyroid Imaging

4/25/2000

CXR PA . LT.


124I I di i Th id C


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124I-Iodine in Thyroid Cancer

277269

229 cGy/mCi203 cGy/mCi

125 cGy/mCi



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Differentiation and Oncofetal Antigens


G250 C b i h d IX h i


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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 G250 (5 Ci 10 )


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124I-cG250 (5 mCi, 10 mg)

6D

Non Contrast (PET/ CT

Fusion

Contrast CT


A33 ti ti ht j ti t i


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A33 antigen: a tight junction protein

Not constitutively

internalized Accumulation in

junctional complex

components Possibly suitable for

multistep targeting

methodsA33-occludin

Courtesy I Mellman, PhD


015 LD


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015:LD

70 YO Female

Presented with anemia. Splenic flexure lesions,hepatic metastasis.

2/6/07 2 foci Adenocarcinoma with mucinousfeature


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I-A33 in Colorectal Ca: uptake in occult

aorto-caval node



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CT

FDGI-124 A33

Fused A33-CT


124I A33 in Primary Colorectal Cancer


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124I-A33 in Primary Colorectal Cancer


010:RK


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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


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010:RK

FDG FUSIONI-124 A33 7 D


Correlation of antigen sites with antibody


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Correlation of antigen sites with antibody

uptake

0 2 4 6

0.000

0.002

0.004

0.006

0.008

0.010

0.012

0.014

0.016

0.018

Ileum

Mid Colon

LN Colon

Tumor

Correlation Between124

I-A33 In VivoUptake

and In VitroDetermination of A33 sites

Data: Data33_B

Model: linear

C hi^2 = 2.7 48 1E -6

R^2 = 0.88546

a 0.00244 0.00088

b 0.00202 0.00027

124I-A33(%I

D/g)

Sites (pmoles/mg)


Images of 124I-A33 (IVIG) in Patient No 13


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Images of I A33 (IVIG) in Patient No.13

ARG(72h expo)

H&E

Section T1S2-10, 6x12mm

Tumor tissue-1 Tumor tissue-2 Tumor tissue-3(Aorta lymph node) (Anterior aortic node) (Vena lymph node)

Section T2S10, 8x11mm

Section T3S8, 7x18mm

Section T1S2-10, 6x12mm Section T2S10, 8x11mm Section T3S8, 7x18mm


MSKCC Novel Antibodies


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A33: Colorectal Cancer

G250: Renal Cancer

F-19: Colorectal; Breast; Pancreatic

3F8: Neuroblastoma; SCLC; Glioma;Melanoma; Sarcoma

M195: AML, PML, CML

MSKCC Novel Antibodies


3F8*


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3F8

Anti-GD2

Neuroblastoma

SCLC

Brain tumors

Osteosarcoma

Drs. NKV Cheung, B. Kushner, K. Kramer, Shakeel Modak


CNS Neuroblastoma Dosimetry and


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y

Treatment with radiolabeled 3F8 antibody

Ludwig Center for CancerImmunotherapy

Pediatric PO1 Cheung and Kramer


Sagittal section from serial 124I-3F8 PET


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images of pediatric patient with neuroblastoma

Quantitative PET images used to estimate the radiation dose

from 50 mCi of131I-3F8.

CSF in 4th ventricle = 2,176 cGy thoracic CSF = 1,004 cGy

4 hours 24 hours 48 hours


Patient #1: Patient #2:


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PFS at 5 yrs PFS at 4 yrs

Salvage Regimen Salvage Regimen


Long standing CR after clearance of CSF and


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MR

1 monthpost 30mCi 131I-8H9



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New Directions Small Molecules


Radiolabeled Small Molecule Inhibitor of


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N

N

N

N

O

O

F

NH

H2N

124I

HSP 90 - [124

I]PU-DZ8

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

i H 90


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in Hsp90

O

NH

Me OMeMe

OMe

O

Me

MeO

OHO

O

NH2

H3CO

Geldanamycin (GM)

NH

Me OMeMe

OMe

O

Me

O

MeO

OHO

O

NH2

HN

17-AAG


124I-PU-DZ8 in Breast Cancer


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3 hours 17 hours


Acknowledgements


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g

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

pet primena

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