Designing a New Radiopharmaceutical

  1. Compatibility
    1. Radioactive tracer must be incorporated into the molecule being labeled
    2. Specific radionuclides will only label certain compounds
    3. Example
      1. 111In will forms a covalent bond with DTPA (chelating agent) under the right circumstances - Link
      2. This occurs when the chelating agent contains nitrogen and oxygen atoms because electrons are needed from both elements which share in the covalent bond
      3. Iodine binds to tyrosyl group in protein
      4. Mercury radionuclides require sulfhydryl groups
      5. Therefore, specific elements/chemicals must be present in order for a bond to occur
      6. Another example - What are your comments on how 99mTc bonds with MDP? Link
  2. Stoichiometry
    1. Is the quantitative relationship between chemicals, their relationship, and how they react physically/chemically
    2. In nuclear pharmacy we should examine the different reagents that are involved in compounding of the radiopharmaceutical
      1. 99mTc - radioactive tracer
      2. Sn+2 - reducing agent (1000 to 1 ratio when comparing Sn+2 to 99mTc )
      3. Chelating agent — DTPA, MDP, MAA, etc.
    3. 99mTc concentration is around 10-9 molar (very small amount)
    4. The amount of Sn+2 is usually much greater than 99mTc.  This is to ensures reduction of the radionuclide
    5. Enough chelating agent must be added to compound and the radiopharmaceutical must be 95% bound (defined as radiopharmaceutical purity)
  3. Size of the radiopharmaceutical
    1. Size can effect the absorption rate into a biological system/organ/disease
    2. As an example, molecules larger than 60,000 molecular weight cannot be filter by GFR
    3. So what is your goal? Do you need to radiopharmaceutical filtered to improve your target to background?
  4. Charge of the molecule
    1. Determines solubility of tracer
    2. Greater charge = aqueous solution
    3. Lesser charge = organic solvents and lipids
    4. Is there advantage to acqueous vs. organic sovent/lipid?
  5. Protein binding
    1. Most drugs to some extent are bound to plasma protein - usually albumin
    2. As an example, 111In and 67Ga are bound to transferrin in the plasma
    3. Also effecting the binding potential of the tracer to the chelating agent are: charge of the radiopharmaceutical molecule, pH, nature of the protein, and concentration of anion in plasma
    4. Transchelation occurs when metal chelates exchanges the metal ion with protein.  This occurs because metal has a very strong affinity for protein
    5. Determining the effects of how much is bound to protein is important because this may adversely effect the biodistribution of the agent
    6. Protein binding and tissue uptake very from from one radiopharmaceuticals to the next.  To the extent that the radiopharmaceutical becomes protein bound will effect the way the tracer actually perfuses into tissue and cells.  To determine the amount of a radiopharmaceutical bound to plasma protein
      1. In vitro mix the radiopharmaceutical with tricholracetic acid, and measuring the amount of precipitate. 
      2. The precipitate is the amount which is protein bound
  6. Solubility
    1. Before injecting the radiopharmaceutical consider its solubility within the human system is essential
      1. It is essential that the aqueous solution being administered IV be similar in pH to the vascular pool (blood pH ~ 7.4)
      2. Ionic strength and osmolality should be suitable for blood
      3. Lipid solubility is essential so that the agent will cross the cell membrane.  Remember cell membranes are composed of lipids, mostly, phospholipids
      4. Usually the radiopharmaceutical is required to cross the cell membrane causing uptake within the cell
      5. As a general role
        1. The greater the drug is protein bond the less lipid soluble it is
        2. The more ionic a radiopharmaceutical the less soluble in lipid
        3. Those drugs that are nonpolar are highly soluble in lipids (think covalent)
      6. Can you think of several exampels of radiopharmaceuticals that are soluble and unsoluble?
  7. Stability
    1. In vivo decomposition of the radiopharmaceutical will alter the biodistribution (after injecting you don't want it to break down)
    2. Other factors that effect the radio-tracer stability are - temperature, light, pH, and amount of radiation being emitted
    3. Example of unstability - Dehalogenated of 131I will create free 131I in the vascular pool. If the iodine is tagged to a renal agent, how would dehalogenation effect its biodistribution?
  8. Biodistribution - consider the following
    1. Radio-agent must be evaluated for its distribution: in tissue (target/non target), plasma clearance, urinary excretion, and fecal excretion
    2. Animal studies are used to initially determine biodistribution
    3. Plasma clearance half-time is important and is inversely proportional to the organ/tissue or disease uptake
    4. Increased excretion results reduced dosimetry

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