1. Technetium is a transition metal with atomic number 43 and it belonging to Group VIIB (Mn, Tc, Re) on the periodic table
2. Its electronic configuration is 1s²2s²2p⁶3s²3p⁶3d¹⁰4s²4p⁶4d⁶5s¹
3. Technetium can exist in nine different oxidation states, -1 to +7, that result from the loss of 4d and 5s orbital electrons or the gain of an electron to the 5s orbit
4. Stability of these oxidation states depends on
   1. Chemical environment (pH)
   2. The type of ligand to which the Tc is chelated to
   3. The most stable forms are + 7 and +4 states
      1. Sulfides (Tc₂S₇)
      2. Oxides (TcO₂, Tc₂O₇)
      3. Halides (TcF₆, TcCl₆, TcBr₄)
      4. Pertechnetate (TcO₄^-)
   4. Technetium complexes in lower oxidation states (+1, +2, and +3) are stabilized by chelation with various ligands

      Tc-99m-sulfur colloid	+7
      Tc-99m-glucoheptonate (GH)	+5
      Tc-99m DTPA	+4
      Tc-99m-DMSA	+3
      Tc-99m HIDA	+3
      Tc-99m PYP	+3
      Tc-99m MDP	+3

   5. Many +5 complexes are found to be stabilized in aqueous media by oxo groups such as TcO³⁺, trans-TcO₂⁺, and Tc₂O₃⁴⁺ that form the central core of the complex
   6. General comment about oxidation and reduction - is a process in which an element or compound either gain or loss electron(s) during a chemical reaction

1. Reduction occurs when an element/compound losses electrons. There are two components: the reduced element and the reducing agent. When the above compound, tin, accepts carbon electrons in the reaction tin dissociates with oxygen forming carbon monoxide. Tin is reduced

2. Oxidation occurs when an element gains electrons in which the extra electrons, coming from the oxygen are given to the magnesium.
1. Technetium in pertechnetate ion, ^99mTcO₄^-
1. Obtained by the elution of the Molly generator
2. Its most stable state is Tc⁺⁷ where it will only bind to Tc-99m sulfur colloid
3. To react with chelation, the Tc⁺⁷ state (which is its oxidation after elution)
   1. Must be reduced to lower oxidation states by reducing agents
   2. Reducing agents that have been used include stannous salts, concentrated HCl, sodium borohydride, sodium diothionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphorus acid, and hydrazine
   3. Stannous salts include tartrate, citrate, chloride, fluoride and pyrophosphate, of which stannous chloride (SnCl₂.2H₂O) is the most common reducing agents
   4. The reduction reaction that takes place with stannous chloride in acidic medium give

   

   1. From the above identify - reduced/reducing agent, chelated production, and HR
   2. Other oxidation states, individually or in mixture, may be formed under different physicochemical conditions. Example - At neutral pH, stannous ions form colloids which are undesirable result in the chelation process of ^99mTc
1. Complex Formation with Reduced ^99mTc
   1. The reduced species of ^99mTc are chemically reactive and form complexes with various chelating agents:
   2. Reduced ^99mTc + Chelating Agent -----> ^99mTc-Chelate
   3. The chelating agent usually donates an ion pair of electrons to form coordinate covalent bonds with ^99mTc
   4. Chelating molecules such as DTPA, macroaggregated albumin (MAA), gluceptate (GH), proteins, and enzymes contain electron donor groups such as - COO^-, -OH^-, -NH₂ and -SH
   5. Remember the chelating agent - donates
2. Pertechnetate in ^99mTc Radiopharmaceuticals
   1. Since not all pertechnetate ions are completely reduced, a small amount of ^99mTcO₄^- is typically present in most ^99mTc radiopharmaceuticals
   2. These free pertechnetate ions are considered radiochemical impurities and may cause artifacts in scintigraphic images. Such as?
   3. The presence of oxygen, free radicals, or other oxidizing agents in the reagent kit may oxidize the stannous ion to stannic ions which compromises the reduction of Tc⁷⁺ resulting in an increase the proportion of free ^99mTcO₄^-
   4. This can be overcome by
      1. Adding a sufficient quantity of Sn²⁺ ions to the kit
      2. Avoiding oxygen, air, or oxidizing agents to the kit
      3. Having nitrogen gas atmosphere in the vial/kit. This removes any oxygen from the vial and eliminates an oxidizing agent
   5. Some kits (MDP, HDP) contain antioxidants (ascorbic acid, gentisic acid) to help further prevent oxidation, especially after the kit has been compounded
3. Hydrolysis of Reduced ^99mTc and Tin
   1. In the absence of sufficient chelating agent, reduced technetium can undergo hydrolysis in aqueous solution at pH 6 or higher forming, such as

   

   2. These products, if present, can reduce label efficiency and interfere with diagnostic interpretation
   3. Sn⁺² ions can undergo hydrolysis in aqueous solution at pH 6-7 to form insoluble colloids. This can be prevented by adding addition chelating agent
4. Preparation of ^99mTc Radiopharmaceuticals by Ligand Exchange
   1. In ligand exchange, transchelation, a ^99mTc complex is first formed with a weak chelate in aqueous media. After chelation has occurred a second reaction is started with a stronger chelating agent. Usually heat has to be added (75^o C to 100^o C) in order for the second chelation event

      

   2. EDTA, tartrate, gluconate, and pyrophosphate are all weak chelating agents, whereas ECD (bicisate), isonitile (MIBI), and MAG₃ are stronger chelating agents
   3. Kits containing both weak and strong chelating agents along with stannous ions include:
      1. Tartrate and MAG₃ for renal imaging
      2. EDTA and ECD for brain imaging
      3. Citrate and MIBI for myocardial imaging
   4. The stronger chelating agents are less soluble in aqueous solution and require heating or a longer time to dissolve
   5. Weaker chelating agents are highly soluble in aqueous solution
      1. The weaker chelating agent is necessary to stabilize the reduced ^99mTc particularly at lower oxidation states
      2. The absence of the weaker chelating agent would lead to the precipitation of the reduced ^99mTc as colloid
5. Chemistry of ^99mTc in Dilute Solutions
   1. In preparations in which the Sn⁺² ion concentration is limited, the total concentration of ^99mTc and ⁹⁹Tc, there may be too high a concentration of ⁹⁹Tc to the complete reaction
   2. In such cases (HMPAO) freshly eluted ^99mTc is required in order to minimize the amount of ⁹⁹Tc present
6. ^99mTc-labeled Peptides and Proteins
   1. Direct Labeling
      1. ^99mTc can be bound to a colloid that is coated with antibody
      2. Colloids are taken up by albumin
      3. ^99mTc can be bound to the sulfhydryl groups in the antibody
      4. A pretinning process whereby the sulfhydryl groups are freed by the reduction of disulfide bonds of the antibody using stannous ion
   2. Indirect Labeling with ^99mTc Complex using Bifunctional Chelators
      1. ^99mTc-chelates are preformed using bifunctional chelating agents [diamidodithio, boronic acid adduct of technetium dioximes (BATO) and cyclam derivatives]
      2. Used to label proteins by forming bonds between chelating agent and the protein
      3. Indirect Labeling using Bifunctional Chelators
      4. A bifunctional chelator (BFC) is conjugated with a macromolecule (protein or peptide) on one side and a metal ion (Tc) by chelation on the other side
         1. BFCs in use include metallothionein, dithiosemicarbazone and diamide dimercaptide (N₂S₂)
         2. The conjugation of the macromolecule takes place between the -NH₂ or -SH group of these macromolecules and one of the reactive sites of the BFC
7. ^99mTc-labeld Red Blood Cells
   1. In vitro method
      1. Blood is drawn from the patient, RBCs are primed with Sn⁺² and then ^99mTcO₄^- is added
      2. Sn⁺² ion enters the RBC and remains bound to hemoglobin
      3. Subsequently Tc⁺⁷ ion enters the RBC and is reduced by Sn⁺²
      4. Reduced-^99mTc binds 80% to the beta chain of globin and 20% to heme. Labeling efficiency is >97%
      5. A commercial kit (UltraTag RBC) is available for this method
   2. In vivo method
      1. Sn⁺² ions in the form of stannous pyrophosphate are administered IV to the patient
      2. After a delay of 30 minutes, ^99mTcO₄^- is administered whereby the labeling occurs in the same manner as in the in vivo method
      3. 10-20 μg/kg body weight of Sn²⁺ ion is required for optimum labeling
      4. Labeling efficiency is 80-90%.
   3. Modified in vitro method
      1. Sn-PYP is administered IV to the patient in whom an infusion set fitted with a three-way stopcock has been placed
      2. One port of the stopcock is connected to a syringe containing heparinized saline (10U/mL) and the other port to a syringe containing ^99mTcO₄^-
      3. Twenty minutes after injection of Sn-PYP, blood is drawn into the ^99mTc-syringe and incubated with several gentle mixing over 10 minutes
      4. Labeled RBCs are injected back into the patient. Label efficiency is >95%
8. ^99mTc labeled Leukocytes and Platelets
   1. ^99mTc-HMPAO (Ceretec)
      1. A neutral lipophilic compound that easily enters the leukocyte by passive diffusion. Freshly prepared ^99mTc-HMPAO is added to separated WBCs in plasma/ACD mixture
      2. After a 15 minute incubation, cells are separated by centrifugation, washed and suspended in plasma for injection. Labeling efficiency is 50-60%
9. ^99mTc Sulesomab (LeukoScan)
   1. A ^99mTc labeled murine antibody fragment (IMMU-MN3) for the nuclear imaging of activated granulocytes
10. ^99mTc Apcitide (AcuTect)
    1. A labeled peptide that binds to GPIIb/IIIa adhesion molecule receptors (of the integrin family) found on activated platelets

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