Radiochemistry of Technetium-99m - NKRV · Radiochemistry of Technetium-99m Otto C. Boerman, PhD...
Transcript of Radiochemistry of Technetium-99m - NKRV · Radiochemistry of Technetium-99m Otto C. Boerman, PhD...
Radiochemistry of Technetium-99m
Otto C. Boerman, PhD
Radboud University Nijmegen Medical Center, The Netherlands
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
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
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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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
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
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
Coordination chemistry of Tc 99mCoordination chemistry of Tc-99m
TcO4-
Sn2+
Tc(V)
Square pyrimidal complex
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Gluconate glucoheptonate
Tc-99m-labeled agents for myocardial perfusionTc 99m labeled agents for myocardial perfusion
99mTc-sestamibi
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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
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
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
Tc-99m labeling via a bifunctional chelate: S-HYNICg
H2N-peptide + peptide-NH
TcO4-
SnCl2Coligand L
peptide
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
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
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.
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
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
• 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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