Labeling with ^99mTc

1. In general

   1. Of all the radionuclides used ^99mTc is the most popular
   2. When imaging with this agent consider the amount of gamma abundance, short half-live, gamma energy, and its ability to tag to other pharmaceuticals
   3. Outline and compare ^99mTc to ¹³¹I
2. Chemistry

   1. Transition metal group VIIB
   2. Decays to ⁹⁹Tc which has a 2.1 x 10 ⁵ years
   3. There are 7 oxidation states: -1 to +7
      1. +7 ( ^99mTcO₄^- and ^99mTc₂S₇) and +4 are the most stable and exist with oxides, sulfides, halides, and pertechnetate
      2. -1, +1, +2 and +3 are stable by complexing with ligands
         1. Tc +1 complexes with sestamibi
         2. Tc +3 complexes with DTPA, EDTA, DMSA, and IDA
         3. Tc +5 complexes to citrate, gluconate, and HMPAO
   4. Reduction of ^99mTcO₄^-
      1. The chemical form of Tc^99m eluded from the generator is known as sodium pertechnetate (Na ^99mTcO₄^-). ^99mTcO₄^- is in the 7+ oxidation state
      2. Reducing agents such as stannous chloride, stannous citrate, stannous tartrate, concentrated HCl, sodium borohydride, dithionite and ferrous sulfate are used to lower the +7 oxidation state to a reactive species:
      
      
      

      3Sn+2		3Sn+4 + 6e-
      299mTcO4- + 16H+ + 6e-		299mTc+4 + 8H2O

      3. Adding pertechnetate with a reducing agent changes it ^99mTc to a +4 valence state (receive)

       

      299mTcO4- + 16H + 3Sn+2

      299mTc+4 + 3Sn+4 + 8H2O

      
      
      4. A sufficient excess of reducing agent must be present to insure complete reduction of both ^99mTc and ⁹⁹Tc atoms
3. Labeling with reduced technetium
   1. Reduced ^99mTc + chelating agent ^99mTc-chelate
   2. The chelating agent must contain groups that donate lon pairs of electrons to form coordinate covalent bonds with reduced ^99mTc. Examples would include: -COO^-, - OH^-, -NH₂, and -SH


4. Free Pertechnetate in ^99mTc radiopharmaceuticals (what might go wrong in the process of compounding?)
   1. The presence of O₂ in vials prior to the addition of ^99mTc causes oxidation of stannous ion to stannic ion hence decreasing the amount of stannous ion available for reduction (from the +7 state to ____ )
   2. High ^99mTc activity in the presence of oxygen causes radiolysis of water with production of hydroxyl (OH), alkoxyl (RO .), and peroxy (RO₂ .) [there are known as free radicals]. These species interact with ^99mTc-chelates producing free ^99mTcO4 ^-
   3. Not enough Sn⁺² in the vial to reduce ^99mTc.
   4. Vial must also be flushed with nitrogen gas and antioxidants to prevent oxidation
   5. Nuclear Medicine personnel must avoid adding room air into vials. Oxygen in the air may act as an oxidation agent
   6. Consider a situation where you are going to draw a dose from a ^99mTc-chelated from a vial. Most health care professionals would add an equal amount of air (from the syringe) to the volume you are going to remove. Therefore keeping the pressure of the vial neutral. In nuclear medicine arena, is that a good idea?
   7. What type of tissues uptake would you expect to visualize if too much pertechnetate was in a vial of MDP?
   8. In the same vial of MDP, when compounding, what would happen if there wasn't enough SnCl₂?
5. Hydrolysis of reduced technetium and tin
   1. Hydrolyzed-reduced technetium (HR-Tc) impurity is characterized by the formation of an insoluble colloidal species:
   TcO₊₂ + 2OH - TcO₂ + H₂O (s)
   
   
   1. This reaction is favored at a neutral pH and at low concentration of chelation agent.
   2. Any uncomplexed stannous ion can also hydrolyze to form insoluble colloidal tin hydroxide:
   
   
   Sn⁺2 + 2OH Sn(OH)₂
   
   
   
   3. Which can subsequently bind reduced ^99mTc.The formation of this colloid would then in RES
   4. Presence of excess chelating agent and favorable pH prevents formation of these impurities
      
   2. Formation of ^99mTc (liquid soluble) complexes by ligand exchange (transchelation)
   1. Ligand exchange labeling is required when the ligand being labeled has poor solubility in an aqueous media or when the labeling reaction takes a long time
      1. Under these circumstances reduced ^99mTc must be temporarily complexed to a weak chelate to prevent formation of ^99mTc impurities
      2. Subsequently, ^99mTc is exchanged from the weak chelate to the ligand of interest
      3. Strong ligands such as MAG 3, isonitriles, ECD are poorly soluble in aqueous media and require heating for dissolution. ^99mTc is first bound to weak chelates such as tartrate, citrate or EDTA and then transferred to primary ligand. The following is an example on how MAG3 is tagged to pertechnetate
      
      

      ^99mTcO4^- + Sn 2⁺ Reduced ^99mTc + Sn4⁺
      
      Reduced ^99mTc + tartrate ^99mTc-tartrate
      
      Tc^99m- tartrate + MAG 3 ^99mTcMAG 3 + tartrate

   3. Radiopharmaceutical kits prepared for radiolabeling with ^99mTc are are made by the manufacturers must contain the following
   1. Compound (chelate) to be labeled
   2. Acidic solution of a stannous compound (chloride, fluoride, citrate, tartrate, pyrophosphate). Tin complexes to the chelate as follows:
   Sn 2⁺ + chelating agent Sn-chelate
   
   1. Too much tin increases the possibility of tin hydrolysis resulting in formation of a ^99mTc-Sn-colloid precipitate.
   2. Too little tin may result in incomplete reduction of ^99mTc
   3. pH adjustment to 5 - 7 with dilute NaOH purged with nitrogen
   4. Lyophilized (freeze dried)
   5. Flushed and filled with sterile nitrogen
6. General Imputities found in a 99mTc-chelated compound
1. Free ^99mTc as ^99mTcO₄^- not reduced by Sn⁺²
2. Hydrolyzed ^99mTc in the form of ^99mTcO₂ that did not react with the chelating agent. This includes ^99mTc bound to hydrolyzed Sn⁺² in the form of Sn(OH)₂
3. ^99mTc-chelated is the desired product

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