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Production, Use and Applications of 124I

Jason S. Lewis, PhDChief, Radiochemistry ServiceDirector, Cyclotron-Radiochemistry CoreMemorial-Sloan Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center

No Financial Disclosures


Presentation

Decay Schemes, Cross SectionsSolid Targetry, Production, Separation MethodsClinical Applications


124I Decay SchemeT½ = 4.176 dat 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)

β+ 0.002 0.820 0.3660.113 1.543 0.6860.113 2.146 0.974

γ 0.605 0.6030.100 0.7230.014 1.3250.017 1.3760.030 1.5090.104 1.691

MIRD Radionuclide Data and Decay Schemes

124I53

124Te (stable)52

β+

β+

β+

γ

γ

γ

γ γ

γ


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 Jülich, Courtesy of Dr. Syed Qaim)

Impurity [%]Nuclear reaction

Energy range [MeV]

Thick target yield of 124I [MBq/µA·h](mCi/µA·h)

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

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

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

121Sb(α,n) 22 → 13 2.1(0.06) 895 <0.2 <0.2

124Te(p,n) 12 → 8 16 (0.43) 1.0 < 0.1 -

123I(13.3 h)

125I(59.4 d)

126I(12.9 d)

125Te(p,2n) 21 → 15 81 (2.19) 7.4

3877

-

natSb(3He,xn) 35 → 13 0.95 (0.03)

0.9

0.6 0.6

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 63Cu2

76Se target.Activity is trapped on quartz tube.Removal of radioactivity by washing with NH4OH.Recovery of radioactivity up to 76%.


Washington University – 76Br

Quartz tube changed every two or three productions

0.000

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

Prod

uctio

n R

ate

(mC

i/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

Perc

ent R

ecov

ered


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


Irradiation Conditions20-degree incline20 mil Platinum foil crucible

200 mg Al2Te3

11 → 2.5 MeV3L/sec circulating chilled helium

30% Power in helium stream

dryice

University of Wisconsin: Sloping Solid Target


Thermal distillation of iodide from Al2124Te3 glassy melt↑ 900o C, sublimation of iodide in air streamTrapped on chilled capillary quartz tube loaded w/Pt wire on a film of weak base

Carbolite Furnace24/40 grindings

Dry iceCharcoal trap15 SCCM

Air

Exhaust

University of Wisconsin: Harvesting Iodine

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


Targetry - Hammersmith Imanet

Courtesy of Mathias Glaser, PhD

O2 Al2O3 Charcoal

NaOH (20 mM)

"Spoon" Furnace tubeFurnace

Protons 12.5 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.

Rel

ativ

e ta

rget

yie

ld, d

ecay

-cor

rect

ed (M

Bq/μ

Ah)

0

50

100

150

200

250

300

350

400

Batch yield (M

Bq)

0 5 10 15 20 25 30 350

100

200

300

400

500

600

700

800

Furnace temperature Detector response

Time (min)

Furn

ace

tem

pera

ture

(o C)

0

1000

2000

3000

4000

5000

Detector response (cpm

)0 5 10 15 20 25 30 35 40

0

50

100

150

200

Rel

ativ

e ta

rget

yie

ld, d

ecay

-cor

rect

ed (M

Bq/μ

Ah)

Integrated beam current (μAh)


State University of New York, Buffalo

Courtesy of Erol Bars, PhD


State University of New York, Buffalo

©20

06

I-124 Production Overview

Nuclear reaction: 124Te (p,n) 124IRoute selected for both high yield and high purity124Te enriched Tellurium Oxide (TeO2) is the target materialmaterialThermo-distillation selected as recovery processRecovery method associated with high recovery yields (90%)(90%)High Specific Activity (No Carrier Added) is desiredHigh radioactive concentration[124I]NaI in NaOH solution (pH of 8.5) prevents volatilizationvolatilizationFlexibility to trap 124I in other solutions, and perform direct direct radio-labeling of precursors

Data prepared byBob Ylimaki, Bernard Lambert, Jean-Michel Geets

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06

I-124 Production

IBA nirta solid target

Optimized for 124TeO2

Low thermal conductivity

He cooling protects

target matrix

Remotely unloaded

©20

06

IBA Nirta Solid target

Target disk 24mm Ø

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06

I-124 Production Process

Target Disk IrradiationOptimal energy range for 124I 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

25µA at 13Mev

Typical irradiation: 10-12 hours

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06

I-124 Production Target Yield

Agreement with predicted 20MBq (0.54mCi)/uAh

124I Production YieldTypical Production Yields

0

10

20

30

40

50

60

70

80

90

100

0 50 100 150 200 250

uA-h

mC

i

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 µA (single)

Dual beam possible

©20

06

I-124 Production Process

124I 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 µl)500 µl)

©20

06

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 acceptanceacceptance

Traceable 152Eu standard used for daily calibration123I 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 1µg/ml

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I-124 Radiolabeled compounds

I-124, NaI solution, activity level up to 20 mCiI-124 MIBGCollaboration : Wilex compound

I-124 Radiolabeled cG250 antibodyRenal cell carcinoma imagingEstimated worldwide 480,000 uncharacterizeduncharacterized renal masses are annuallyidentifiedPrevents unnecessary nephrectomies

I-124 ??Other compounds

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06

124I – IBA production centers

IBA VCU, Richmond

VU, Amsterdam

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06

IBA Radioisotopes - Belgium

Fleurus facility: (14MeV- 1mA)

R&D center and radioisotopes production center


GEMS – NIH and Tubingen


ACOM (Italy)


124I Production SummaryCenter Energy

(MeV)Experimental Yield

(mCi/μAh)Typical

runActual activity

(mCi)ACOM 15.4 0.49 - 0.52 (n=10)

60 - 64% theor.12 μA/8h 50.9 - 56.8

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

Wisconsin 11.0 0.23 18 μA/4h 12.0Jülich 16.0 0.16 10 μA/8h 12.7

100.0

15 - 25WUSTL 12.5 0.26 ± 0.02 ~30Essen 14.0 15 μA/2h

~110.0

IBA 13.0 0.5 (93% theor.) 25 μA/8h

NIH 12.5 0.018 ± 0.005 (n = 4)

Tübingen 15.0 0.15 ± 0.02 (n = 24)MSKCC 14.7 0.54 25 μA/68h

Buffalo 14.1 0.53 – 0.64(90% theor.)

24 μA/8h

ACOM, IBA – 18 MeV IBA cyclotron using COSTIS; Buffalo – 30 MeV IBA cyclotron; NIH, Tübingen – GE PETtrace; MSKCC – EBCO TR19; WUSTL – CS15; Wisconsin – CTI 11 MeV; Essen – CS28; Hammersmith – Scanditronix MC40


Target Substrates and YieldsCenter Target

(mg)Substrate Enrichment Al2O3 w/w

(%)

99.50 5

66.75

6

55.2

99.3

99.86

99.899.899.7

96.099.5

99.899.86

Isolation Yield

90%

90%

70 ± 5%31%

80%65%95%

89 ± 5%

TeO2

TeO2

TeO2

Cu2TeTeO2

TeO2

Al2Te3

TeO2

TeO2

Specific Activity

(Ci/μmol)ACOM 260

Hammersmith 1100 0.746

Wisconsin 200

Jülich 200

IBA

Tübingen 600MSKCC 200 >30WUSTL

Essen

Buffalo 600


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., EurRadiology 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)


Clinical Applications124I-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., Lancet Oncology. 2001;358:729-29)124I-IUdR 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]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 Ca4/28/00 Papillary thyroid Ca, moderately differentiated, locally invasive, 2.0 cm in diameter, with 13/23 lymph nodesRefered for Dosimetry 7/2000


124I Thyroid Imaging

4/25/2000

CXR PA . LT.


124I-Iodine in Thyroid Cancer

277269

229 cGy/mCi203 cGy/mCi

125 cGy/mCi


Clinical Applications

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

Non Contrast (PET/CT

Fusion

Contrast CT


A33 antigen: a tight junction protein

Not constitutively internalizedAccumulation in junctional complex componentsPossibly suitable for multistep targeting methods

A33-occludin

Courtesy I Mellman, PhD


015:LD70 YO FemalePresented 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 cmLiver metastasis #3 largest 3.1 cm9/12/07 NED on chemo


124I-A33 in Colorectal Ca: uptake in occult aorto-caval node


CT

FDGI-124 A33

Fused A33-CT


124I-A33 in Primary Colorectal Cancer


010:RK

65 yo presented with rectal cancer stage IV to the liver at presentation 9/5/02Initial surgery 5/29/03 rectum and liverRecurrent liver metastasis11/22/2005 Liver Metastatic adenocarcinoma consistent with colorectal 4.1 cm. and concurrent : Metastatic disease to lymph node


010:RK

FDG FUSIONI-124 A33 7 D


Correlation of antigen sites with antibody uptake

0 2 4 60.000

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 Between 124I-A33 In Vivo Uptake and In Vitro Determination of A33 sites

Data: Data33_BModel: linear Chi^2 = 2.7481E-6R^2 = 0.88546 a 0.00244 ±0.00088b 0.00202 ±0.00027

124 I-

A33

(%

ID/g

)

Sites (pmoles/mg)


Images of 124I-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


A33: Colorectal CancerG250: Renal CancerF-19: Colorectal; Breast; Pancreatic3F8: Neuroblastoma; SCLC; Glioma; Melanoma; SarcomaM195: AML, PML, CML

MSKCC Novel Antibodies


3F8*

Anti-GD2NeuroblastomaSCLCBrain tumorsOsteosarcoma

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


CNS Neuroblastoma Dosimetry and Treatment with radiolabeled 3F8 antibody

Ludwig Center for Cancer ImmunotherapyPediatric PO1 Cheung and Kramer


Sagittal section from serial 124I-3F8 PET images of pediatric patient with neuroblastoma

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

4 hours 24 hours 48 hours


PFS at 5 yrs PFS at 4 yrs

Patient #1: Patient #2:

Salvage Regimen Salvage Regimen


Long standing CR after clearance of CSF and MR

1 monthpost 30 mCi 131I-8H9


New Directions – Small Molecules


N

N

N

N

O

O

F

NH

H2N

124I

Radiolabeled Small Molecule Inhibitor of HSP 90 - [124I]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 in Hsp90

O

NH

Me OMeMe

OMe

OMe

MeOOH O

ONH2

H3CO

Geldanamycin (GM)

NH

Me OMeMe

OMe

OMe

O

MeOOH

OONH2

HN

17-AAG


3 hours 17 hours

124I-PU-DZ8 in Breast Cancer


AcknowledgementsHoward Sheh and the Cyclotron Team - MSKCCDrs. Steven Larson and Jorge Carrasquillo – MSKCCDr. Gabriela Chiosis - SKIDrs. Peter Smith-Jones and Kishore Pillarsetty - MSKCCDr. Syed Qaim – Forschungszentrum JülichDr. Paola Panichelli – ACOM Spa, ItalyDr. Jerry Nickels – University of WisconsinDr. Mathias Glaser – Hammersmith Imanet LtdDrs. Bob Ylimaki, Bernard Lambert, Jean-Michel Geets – IBADr. Erol Bars – State University of New York, BuffaloLucie Tang – Washington UniversityDrs. Uno Zetterbery, Erik Stromqvist, Armando Sera - GEMS

new production, use and applications of i - home | triumf · 2008. 9. 24. · 2 al 2 o 3 charcoal...

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