Radiochemistry of Technetium-99m

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Radiochemistry of Technetium-99m Otto C. Boerman, PhD Radboud University Nijmegen Medical Center, The Netherlands

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Page 1: Radiochemistry of Technetium-99m

Radiochemistry of Technetium-99m

Otto C. Boerman, PhD

Radboud University Nijmegen Medical Center, The Netherlands

Page 2: Radiochemistry of Technetium-99m

Radboud University Nijmegen Medical Center, The Netherlands

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Radboud University Nijmegen Medical Center, The Netherlands

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Radboud University Nijmegen Medical Center, The Netherlands

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TechnetiumTechnetium

- 1850: Dimitri Mendeleev: Em- 1846-1908: Ilmenium, Pelopium, Davyum, Nipponium- 1925: Noddack et al.: Masurium- 1937: Perrier & Segre: Panormium τεχνητοζ1937: Perrier & Segre: Panormium, τεχνητοζ

- Oxidation state: 0, 1+, 2+, 4+, 5+, 6+, 7+

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- 1962: Kenna & Kuroda - pitchblende Congo: 0.2 ng/kg

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Technetium-99mTechnetium 99m

• 99mT i t t bl t t f t h ti 99 (99T ) ith• 99mTc is a metastable state of technetium-99 (99Tc) witha half-life of 6.02 hours.

• decay to the ground state of 99Tc: 90% emission ofdecay to the ground state of Tc: 90% emission ofgamma photons of 140 keV

Mo-99

T 99Tc-99m

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Tc-99

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Radiation exposure from Tc 99mRadiation exposure from Tc-99m

• The specific gamma ray constant for Tc-99m is 2 mGy / hour.MBq at 1 cm

• The half-value layer is 0.17 mm lead • C t l f th di ti• Control of the radiation exposure:

reduction factor

0.5 0.1 0.01 0.001 0.0001factormm Pb 0.17 0.8 1.6 2.5 3.3

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Production of Technetium 99mProduction of Technetium-99m

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Development of Tc 99m generator at BNLDevelopment of Tc-99m generator at BNL

Powell "Jim" Richards and Walter Tucker

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Powell Jim Richards and Walter Tucker

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Tc-99m generatorTc 99m generator

- Technetium 99m (99mTc) is a decay product of molybdenum-99 (t½ = 66 h)Obt i d b l ti it f l bd 99 t

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- Obtained by eluting it from a molybdenum-99 generator

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Labeling halfproducts with Tc 99mLabeling halfproducts with Tc-99m

• Reduction of TcO4-

• Reductor: Sn2+, Fe2+ TcO4-

• Incubation with halfproduct• Quality control

• Radionuclidic purity: breakthrough of Mo-99740 k V h t 0 5 l d d lib t740 keV photons, 0.5 cm lead, dose calibrator

• ITLC: stationary phase silicagel

TcO2

• ITLC: stationary phase – silicagelmobile phase – 0.1 M ammonium acetate, pH 5.5

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Coordination chemistry of Tc 99mCoordination chemistry of Tc-99m

TcO4-

Sn2+

Tc(V)

Square pyrimidal complex

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Gluconate glucoheptonate

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Tc-99m-labeled agents for myocardial perfusionTc 99m labeled agents for myocardial perfusion

99mTc-sestamibi

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Tc-99m-labeled agents for cerebral perfusionTc 99m labeled agents for cerebral perfusion

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Tc 99m labeled agents for renal functionTc-99m-labeled agents for renal function

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Tc 99m demotateTc-99m-demotate

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Tc-99m-Methylene diphosphonate (MDP)Tc 99m Methylene diphosphonate (MDP)

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Labeling antibodies peptides and small molecules with Tc 99mLabeling antibodies, peptides and small molecules with Tc-99m

Direct labeling method:

Using free sulfhydril groups of the biomolecule to chelate Tc-99m

(Schwarz method, iminothiolane method)

Bifunctional chelate method:Bifunctional chelate method:

Modification of biomolecule with bifunctional chelating agent

(HYNIC, MAG3, tetraamine, a.o.)

Hybrid method:

Incorporating tripeptide sequence (Gly3, Cys-Gly-Gly, Cys-Gly-Cys) to introduce a

N4, N3S, N2S2 donor set

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Schwarz method: a direct labeling methodSchwarz method: a direct labeling method

• Incubate Ab with β-ME (1000:1)

30 i RT30 min, RT

• Purify Ab by Gelfiltration

• Add transchelator

(gluconate, MDP, tricine)

• Add TcO4-

• Incubate 10 min, RT

• QC with ITLC

M th & Elli J N l M d 1990 31 692 697

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Mather & Ellison. J Nucl Med 1990; 31: 692-697

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Iminothiolane method: a direct labeling methodIminothiolane method: a direct labeling method

protein protein

Patricio et al Q J Nucl Med 1995; 39: 74-75

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Patricio et al. Q J Nucl Med 1995; 39: 74-75

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Tc 99m labeling via a bifunctional chelate: S MAG3Tc-99m labeling via a bifunctional chelate: S-MAG3

H2N-peptide +0.1 M NaHCO3pH 8.5

Hpeptide-N

TcO4-

RTTricine/tartrate

99TcH

Hnatowich et al J Nucl Med 1998; 39: 56-64 Hpeptide-N

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Hnatowich et al. J Nucl Med. 1998; 39: 56-64 pep de N

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Tc-99m labeling via a bifunctional chelate: S-HYNICg

H2N-peptide + peptide-NH

TcO4-

SnCl2Coligand L

peptide

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Tc-99m-Interleukin-8

I t l ki 8Interleukin-8

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Tc-99m-Interleukin-8

Interleukin-8

8 h4 h2 h1 h1 min

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Tc 99m labeling via HYNIC using different coligandsTc-99m labeling via HYNIC using different coligands

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Rennen et al. Bioconj Chem. 2002; 13: 370

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99mTc-IL-8: Effect of the coligandTc IL 8: Effect of the coligand

Tricine EDDA TPPTS Nicotinic Isonicotinic

Abscess/background ratio:

15 23 4 22 29

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The coordination of Tc 99m in HYNIC conjugatesThe coordination of Tc-99m in HYNIC-conjugates

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King et al. Dalton Trans. 2007; 43:4998-5007.

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Tc 99m labeling using the hybrid methodTc-99m labeling using the hybrid method

P483: Ac-Lys-Lys-Lys-Lys-Lys-Cys-Gly-Cys-Gly-Gly-Pro-Leu-Tyr-Lys-Lys-Ile-Ile-Lys-Lys-Leu-Leu-Glu-Ser

Incubate peptide with TcO4- glucoheptonate

0.9% NaCl, 20 min, 95 °C0.9% NaCl, 20 min, 95 C

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Tc 99m labeling using the hybrid methodTc-99m labeling using the hybrid method

P829: cyclo-(N-Me)Phe-Tyr-D-Trp-Lys-Val-Hcy(CH2CO-β-Dap)-Lys-Cys-Lys-NH2

Incubate peptide with TcO4- glucoheptonate

0.9% NaCl, 20 min, RT

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Tc 99m labeling using the tricarbonyl methodTc-99m labeling using the tricarbonyl method

Formation of Tc(CO)3(H2O)3 complexLabeling of (modified) peptide with the Tc(CO)3(H2O)3 complex

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- Alberto, Schibli, Egli, Schubiger. PSI Villigen, ETH Zurich

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Waibel et al. Nat Biotechnol. 1999 ;17:897-901

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Tc-99m labeling using the tricarbonyl methodTc-99m labeling using the tricarbonyl method

Synthesis of 99mTc(CO)3(H2O)3+

Reduce TcO4- with NaBH4 and CO (1 atm), 30 min at 75 °CReduce TcO4 with NaBH4 and CO (1 atm), 30 min at 75 C

or using with Isolink™ kit: K2[H3BCO2], 30 min at 100 °C

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Tc 99m labeling using the tricarbonyl methodTc-99m labeling using the tricarbonyl method

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Tc-99m labeling using the tricarbonyl methodTc 99m labeling using the tricarbonyl method

• Label (modified) peptide with Tc(CO)3(H2O)3+ at 2 mg/ml

• Mix 1 : 2 with 0.5 M MES, pH 6.2

• Add 99mTc(CO) (H O) +Add 99mTc(CO)3(H2O)3

• Incubate 15-30 min at 37 °C

• Labeling efficiency: 70-95 %

• Purify the labeled peptide

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99mTc IL 8 in rabbits with i m E Coli infection99mTc-IL-8 in rabbits with i.m. E.Coli infection

99mTc-HYNIC-IL-8 99mTc(CO)3-IL-8