Radiopharmaceuticals for – CNS

Radiopharmaceuticals for evaluation of CNS can be divided into (1) non diffusible tracers, (2) diffusible tracers, (3) metabolism markers, (4) CSF agents, and (5) receptor imaging agents.

Non diffusible Tracers

  1. Sodium pertechnetate 99mTc Injection
    1. Compounding- A sterile aqueous solution of 99mTc and 99Tc as sodium pertechnetate in 0.9% sodium chloride injection obtained from the 99Mo/99mTc generator. Its pH is 4.5 – 7.5. Mo-99 activity must not exceed 0.15 μCi per mCi 99mTc at the time of patient dosage administration. Aluminum ion must not exceed 10 μg/mL. Expiration time for sodium pertechnetate injection, and any kit prepared with it, must not exceed 12h from the time of generator elution. The expiration time of the generator is 14d.
    2. Localization – Excluded from entering the normal brain by an intact blood-brain barrier (BBB). However, under conditions in which the barrier is disrupted by brain pathology, the tracer leaves the vascular space and concentrates in the lesion.
      1. Consider the concept known as the sieve effect in which the tracer becomes trapped in the damaged issue along the blood brain barrier
      2. Elimination of the tracer also is important because it reduces the vascular and interstitial fluid activity so that damaged tissue in the brain can be visualized
    3. Clinical use – Brain imaging (10 – 20 mCi), thyroid (1 – 10 mCi), cystography (0.5 – 1 mCi), dacryoscintigraphy (100 μCi), Meckel’s diverticulum (5 – 15 mCi)
    4. Biodistribution – (1 hr post iv infusion) 30% gastric mucosa and mucous neck cells but not peptic (chief) cells or oxyntic (parietal) cells, 2% thyroid, 5% salivary glands and saliva, intestines, choroids plexus.
    5. Excretion- Eliminated by urinary and fecal routes: Cumulative excretion is 30% in 1 day (27% urine, 3% fecal), 72% in 4 days (31% urine, 41% fecal), 90% in 8 days (34% urine, 56% fecal). Excreted in human milk and breast-feeding should be suspended for 48 hours. Undergoes placental transfer.
    6. 9mTc Pertechnetate and 99mTc Gluceptate are the other two non diffusible tracers that can be used in brain imaging
      1. When labeled in the fashion the body can elininate the radiopharmaceutical faster allowing for a reduction in the for delayed imaging
      2. See renal radiopharmaceuticals (link to be established) for more information on these agents
Diffusible Tracers
  1. 99mTc Exametazime Injection (Ceretec) (HMPAO)
    1. Compounding – A sterile aqueous solution prepared from a kit containing a sterile lyophilized mixture of exametazime (0.5 mg), stannous chloride dihydrate (7.6 μg), and sodium chloride (4.5 mg) sealed under nitrogen. The kit also contains one vial each of 1% methylene blue and a phosphate buffer that, when mixed together, act as a stabilizer. The kit is stored at 15 – 25 °C before labeling and at 20 – 25 °C after labeling.
    2. Can be prepared with or with a stabilizer
      1. The stabilized product is prepared by mixing 0.5 mL of methylene blue 1% (free radical scavenger and oxidizer of excess stannous ion) with 4.5 mL of phosphate buffer.
      2. The lyophilized kit is reconstituted with 10 – 54 mCi of 99mTc sodium pertechnetate, followed within 2m by the addition of 2 mL of the methylene blue/buffer mixture. The product is filtered through a 0.45 μm membrane to remove any particulates not visible due to the blue coloration. The product is stable for 4 hours.
      3. The unstabilized product is prepared by reconstituting the lyophilized powder with 10 – 54 mCi 99mTc sodium pertechnetate in a volume of 5 mL. The product is stable for 30 minutes.
      4. For brain imaging, the eluted 99mTc sodium pertechnetate must not be more than 2 hours old from a generator that was eluted within the past 24 hours.
      5. For WBC labeling, the eluted 99mTc sodium pertechnetate must not be more than 2 hours old from a generator that was eluted within the past 24 hours.
      6. Radiochemical purity is (NLT) 80% at 2 hours.
      7. The complex breaks down in time to a secondary complex that does not cross the BBB. The compound must be used within 30 minutes of preparation. Breakdown is associated with
        1. High pH (9 to 9.8)
        2. Presence of hydroxy free radicals
        3. Excess stannous ion.
      8. Addition of phosphate buffer (lowers pH to 6) and methylene blue (free radical scavenger and oxidizes excess stannous) stabilizes the kit for 4 hours.
    3. Localization –
      1. Passive diffusion. Tc99m d ,l-HMPAO (and not the meso isomer) has the capacity to enter normal brain through an intact BBB.
      2. 72% extraction occurs during first pass at rest and extraction decreases at higher flow rates
      3. It is a neutral lipophilic complex that passively diffuses through the endothelial cells of the brain’s capillaries. It enters normal brain (gray matter and basal ganglia) in proportion to regional cerebral blood flow (rCBF). In the brain, the primary complex is converted into a secondary complex that is unable to cross back over the BBB. (In essences, it is converted to a hydrophilic that locks the agent into the cell)
      4. Approximately 15% of the agent is initially hydrophilic (from the vial) which cannot cross the BBB when injected. Taking this into account (15%) the rCBF nature of the radiotracer is almost linear
      5. Regions of normal brain that are adequately perfused demonstrate uptake of radioactivity, whereas brain lesions (i.e., infarcts) that have diminished or absent blood flow appear as areas of decreased radioactivity.
      6. Approximately 4.1% if the radiotracer localizes in the brain which reaches equilibrium in about 2 minutes and remains at that level for about 8 hours
    4. Clinical use – Altered cerebral perfusion in stroke (10 – 20 mCi)
    5. Biodistribution – Brain (4% of i.d). Retention is due to glutathione-mediated conversion of the d ,l-lipophilic complex to a hydrophilic form that cannot diffuse out), myocardium, subcutaneous fat, liver, skeletal muscle.
    6. Excretion – Urinary (2.5% in 20 min, 35% in 24 h, 40% in 48 h), hepatobiliary (30% in GI tract immediately after injection, 15% of this is excreted by 48 h).
  1. 99mTc Bicisate Injection (Neurolite)
    1. Components of the kit
      1. A sterile aqueous solution prepared from kit containing in Vial A: lyophilized mixture of bicisate hihydrochloride(as l,l-ECD) (0.9 mg), disodium edetate dihydrate (0.36 mg) (to stabilize stannous ion), mannitol (24 mg), and stannous chloride dihydrate (72 μg), adjusted to pH 2.7 and sealed under nitrogen
      2. Vial B: Phosphate buffer at pH 7.6
      3. The kit stored at 15 – 25 °C and protected from light.
    2. Labeling is a three-step process:
      1. Adding 100 mCi 99mTc sodium pertechnetate in a 2 mL volume to Vial B (Phosphate buffer vial) to optimize pH.
      2. Adding 3 mL 0.9% sodium chloride injection to Vial A
      3. Within 30s, removing 1 mL from Vial A and adding it to Vial B.
      4. The final mixture is allowed to incubate for 30m at room temperature.
      5. No less than 50 mCi 99mTc sodium pertechnetate should be used in the preparation.
      6. The labeled product is stored at 15 – 25 °C and must be used within 6h of preparation. Radiochemical purity must be ≥ 90%.  
    3. Pertechnetate first forms 99mTc EDTA followed by transchelation to 99mTc ECD.
    4. Localization
      1. Similar to HMPAO
      2. It is species specific and is only know to localize in monkeys and humans
      3. rCBF type agent and is lipophilic
      4. Extraction in first pass is between 47 and 60 percent
      5. Gray to white matter ratio is 4.5 to 1
      6. The radiotracer reaches about 6.5% (max amount) in 5 minutes then slowly declines over time to 3.5% in 4 hours
    5. Clinical use
      1. Adjunct to CT and MRI in the localization of stroke.
      2. While not identified in the package insert ECD has the same clinical applications as HMPAO
        1. Biodistribution – Brain (6.5% of i.d.). Retention is due to metabolism of the l ,l-isomer to a monoacid ester that is trapped in cell cytosol. This agent has similar biodistribution to HMPAO.
        2. Excretion – Urinary (75% within 24 h) and fecal (11% in 48 h).
  1. Thallous Chloride Tl 201 Injection
    1. Metabolism markers
    2. Shows uptake in tumors
    3. Uptake due to increased mitochondria located in tumor
  2. Fludeoxyglucose F-18 Injection
    1. Compounding – Deoxyglucose is labeled with F-18 by nucleophilic displacement of an acetylated sugar derivative (1 ,3,4,6-tetra-O-acetyl-2-O-trifluormethane-sulfonyl-β-D-mannopyranose) followed by hydrolysis.
    2. Localization – Facilitated diffusion by glucose transporter. Transported across the capillary endothelium into the brain interstitial fluid and subsequently into the neuronal cytoplasm. In the cytoplasm, FDG undergoes enzymatic metabolism, with the first step being phosphorylation by hexokinase to FDG-6-phosphate. Further metabolism cannot proceed and it is trapped in tissue.
    3. Clinical use – Measuring regional cerebral glucose utilization ( rCMRglc), assess brain disorders ( dementials, Parkinson’s disease and epilepsy), diagnosis and staging Ca, determine whether a previously respected or radiation-treated brain tumor has become viable (6- 15 mCi)
    4. Fasting for 4 – 6h prior to examination increases the amount of FDG delivered to the brain.
      1. Heart – Optimized if patients are glucose loaded. Under fasting conditions with normal plasma levels of fatty acids, only the ischemic areas of the myocardium use glucose preferentially and, therefore, only these areas will be visualized.
      2. Whole-body imaging – Fasting for several hours prior to study is recommended.
    5. Biodistribution – FDG accumulates mainly in the heart and brain because of the high glycolytic rate of these tissues; it also accumulates throughout the body in proportion to glucose metabolism.
      1. Brain – Gray-to-white matter ratio is 2.1 at 90 m.
    6. Excretion – Does not undergo tubular reabsorption (as does glucose) and is excreted in the urine.

CSF agents

  1. In-111 Pentetate Injection (In-111 DTPA)
    1. Compounding – A sterile aqueous solution of NCA 111-In 3+ complexes to disodium pentetate in a 1:1 molar ratio. The single-use product, available in a 1.5 mL vial, contains in each mL of isotonic solution at the time of calibration 1 mCi In-111, 20 – 50 μg pentetic acid, and sodium bicarbonate with the pH adjusted to 7 – 8. It is stored at 5 – 30 °C. Radiochemical purity is NLT 90%. The Radionuclidic purity at calibration time is NLT 99.88% In-111 and less than 0.06% In-114m and Zn-65 combined.
    2. Clinical use – Radionuclide cisternography (hydrocephalus), CSF leak (500 μCi)
    3. Biodistribution – After injection in the lumbar subarachnoid space, In-111 DTPA moves slowly, with the natural flow of spinal fluid, away from the injection site toward the head. In normal human subjects, the tracer migrates first to the basal cisterns (appears in 1 h and peaks at 4 h). Tracer then flows over the cerebral convexities to the parasagittal region (appears in 4 h and peaks at 14-17 h). Tracer enters the vascular system at the arachnoid granulations.
    4. Excretion – Upon absorption into blood, In-111 DTPA follows normal          urinary route of excretion through glomerular filtration. Urinary excretion is 65% in 1 day, 85% in 3 d.
  1. Receptor imaging agents – Bind to receptors within the brain.
    1. Indications – Detection and quantitation of biochemical function in the brain. Diseases are thought to be associated with changes in the concentration of receptors (up- or down-regulated), which could be measured with an appropriate receptor-binding radiotracer.
    2. Radiopharmaceuticals – C-11 – methylspiperone can measure the occupancy rate of dopamine receptors in the brain.
    3. 99mTc TRODAT localizes in the basal ganglia through its ability to bind    to the dopamine transporter (DAT) in the brain.
    4. Schizophrenia, tardive dyskinesia, and Huntington’s chorea are thought to be associated with an increase in dopamine receptor concentration, while Parkinson’s disease is associated with a decrease in dopamine receptors.

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