Radiochemistry of Technetium-99m Otto C. Boerman, PhD Radboud University Nijmegen Medical Center, The Netherlands
Radboud University Nijmegen Medical Center, The Netherlands
Radboud University Nijmegen Medical Center, The Netherlands
Radboud University Nijmegen Medical Center, The Netherlands
Technetium - 1850: Dimitri Mendeleev: Em - 1846-1908: Ilmenium, Pelopium, Davyum, Nipponium - 1925: Noddack et al.: Masurium - 1937: Perrier & Segre: Panormium, τεχνητοζ - Oxidation state: 0, 1+, 2+, 4+, 5+, 6+, 7+ - 1962: Kenna & Kuroda - pitchblende Congo: 0.2 ng/kg 5
Technetium-99m 99m Tc is ametastable t state t of technetium-99 ti ( 99 T) Tc) with a half-life of 6.02 hours. decay to the ground state of 99 Tc: 90% emission of gamma photons of 140 kev Mo-99 Tc-99m Tc-99 6
Radiation 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 Control of the radiation exposure: reduction factor 0.5 0.1 0.01 0.001 0.0001 mm Pb 0.17 0.8 1.6 2.5 3.3 7
Production of Technetium-99m 8
Development of Tc-99m generator at BNL Powell "Jim" Richards and Walter Tucker 9
Tc-99m generator - Technetium 99m ( 99m Tc) is a decay product of molybdenum-99 (t½ = 66 h) - Obtained by eluting it from a molybdenum-99 generator 10
Labeling halfproducts with Tc-99m Reduction of TcO 4 - Reductor: Sn 2+, Fe 2+ TcO 4 - Incubation with halfproduct Quality control Radionuclidic purity: breakthrough of Mo-99 740 kev photons, 0.5 cm lead, dose calibrator TcO 2 ITLC: stationary phase silicagel mobile phase 0.1 M ammonium acetate, ph 5.5
Coordination chemistry of Tc-99m TcO 4 - Sn 2+ Tc(V) Square pyrimidal complex Gluconate glucoheptonate 12
Tc-99m-labeled agents for myocardial perfusion 99m Tc-sestamibi 13
Tc-99m-labeled agents for cerebral perfusion 14
Tc-99m-labeled agents for renal function 15
Tc-99m-demotate 16
Tc-99m-Methylene diphosphonate (MDP) 17
Labeling 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: Modification of biomolecule with bifunctional chelating agent (HYNIC, MAG 3, tetraamine, a.o.) Hybrid method: Incorporating tripeptide sequence (Gly 3, Cys-Gly-Gly, Cys-Gly-Cys) to introduce a N 4, N 3 S, N 2 S 2 donor set 18
Schwarz method: a direct labeling method Incubate Ab with β-me (1000:1) 30 min, RT Purify Ab by Gelfiltration Add transchelator (gluconate, MDP, tricine) Add TcO 4 - Incubate 10 min, RT QC with ITLC Mather & Ellison. J Nucl Med 1990; 31: 692-697 697 19
Iminothiolane method: a direct labeling method protein protein Patricio et al. Q J Nucl Med 1995; 39: 74-75 20
Tc-99m labeling via a bifunctional chelate: S-MAG3 H 2 N-peptide + 0.1 M NaHCO 3 ph 8.5 peptide-nh TcO 4 - RT Tricine/tartrate 99 Tc Hnatowich et al. J Nucl Med. 1998; 39: 56-64 peptide-n NH H 21
Tc-99m labeling via a bifunctional chelate: S-HYNIC H 2 N-peptide + peptide-nh TcO 4 - SnCl 2 Coligand L peptide
Tc-99m-Interleukin-8 Interleukin-8
Tc-99m-Interleukin-8 Interleukin-8 1 min 1 h 2 h 4 h 8 h
Tc-99m labeling via HYNIC using different coligands Rennen et al. Bioconj Chem. 2002; 13: 370 25
99m Tc-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-conjugates King et al. Dalton Trans. 2007; 43:4998-5007. 27
Tc-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 TcO 4- glucoheptonate 0.9% NaCl, 20 min, 95 CC 28
Tc-99m labeling using the hybrid method P829: cyclo-(n-me)phe-tyr-d-trp-lys-val-hcy(ch 2 CO-β-Dap)-Lys-Cys-Lys-NH 2 Incubate peptide with TcO 4- glucoheptonate 0.9% NaCl, 20 min, RT 29
Tc-99m labeling using the tricarbonyl method Formation of Tc(CO) 3 (H 2 O) 3 complex Labeling of (modified) peptide with the Tc(CO) 3 (H 2 O) 3 complex - Alberto, Schibli, Egli, Schubiger. PSI Villigen, ETH Zurich 30
Waibel et al. Nat Biotechnol. 1999 ;17:897-901 31
Tc-99m labeling using the tricarbonyl method Synthesis of 99m Tc(CO) 3 (H 2 O) 3 + Reduce TcO 4- with NaBH 4 and CO (1 atm), 30 min at 75 C or using with Isolink kit: K 2 [H 3 BCO 2 ], 30 min at 100 C 32
Tc-99m labeling using the tricarbonyl method 33
Tc-99m labeling using the tricarbonyl method Label (modified) peptide with Tc(CO) 3 (H 2 O) 3 + at 2 mg/ml Mix 1 : 2 with 0.5 M MES, ph 6.2 Add 99m Tc(CO) (H O) + Add 99m Tc(CO) 3 (H 2 O) 3 Incubate 15-30 min at 37 C Labeling efficiency: 70-95 % Purify the labeled peptide 34
99m Tc-IL-8 8inrabbits with im i.m. EColiinfection E.Coli infection 99m Tc-HYNIC-IL-8 99m Tc(CO) 3 -IL-8