1. INTRODUCTION
1.8. Summary of a new class of PET tracers
A more detailed description of many new PET tracers is provided in Section 9. Three broad categories of PET tracers are emerging: metabolic agents, receptor agents and peptides. The clinical usefulness of many of these new PET tracers is still under consideration.
1.8.1. Metabolic agents
For metabolic PET agents, the following factors are relevant:
(1) Clinical importance of the target metabolism — the target metabolism should represent a specific cell condition or pathological state.
(2) The agent should accumulate in special cells due to the metabolic procedure.
(3) Rapid clearance from blood and non-target tissues is mandatory.
(4) A sufficiently high specific activity is required, although the importance of this is lower than for other agents.
(5) For whole body PET, excretion through the kidneys is preferable to excretion through the hepatobiliary tract.
Imaging the metabolism of cells is the most common and efficient method currently in the clinical field (Table 4).
Among the metabolic PET agents, 18F-FDG achieved the greatest success, which provided the major momentum for the promotion of PET.
Another eminently successful metabolic PET agent in the clinical fieldsis
11C-methionine.
Metabolic agents are taken up by the cells that use them as a fuel for energy metabolism or building blocks for biosynthesis. Thus, each PET agent should represent the target metabolism accurately.
In general, the capacity of cells to take up the metabolic PET agent is higher relative to other PET agents such as receptor binding agents. This is due to the continuous spend (consumption or utilization) of the metabolic PET agent. Thus, the specific activity of the agent is less important than those for receptor binding agents. However, the specific activity of metabolic agents such as 18F-fluorodopa can be too low because it is labelled by carrier added 18F gas.
1.8.2. Receptor agents
For receptor PET agents, the following factors are relevant:
(a) The clinical importance of the target receptor — the target receptor should represent a specific cell condition or a pathological state.
(b) Brain PET receptor agents require high lipophilicity for easy penetration through the blood–brain barrier. Log P should be between 2 and 4, where P is the partition coefficient.
(c) Brain PET receptor agents require a low molecular weight, preferably less than 500 daltons, for easy penetration through the blood–brain barrier.
(d) A high affinity to the target receptor is mandatory.
(e) A high specificity to a target receptor is recommended.
(f) No or a low metabolism is required for accurate receptor imaging.
(g) Rapid clearance from blood and non-target tissues is mandatory.
(h) For whole body PET, excretion through the kidneys is preferable to excretion through the hepatobiliary tract.
TABLE 4. PET AGENTS FOR IMAGING METABOLISM
Metabolism PET agent
Glucose 18F-FDG
Amino acid 11C-methionine, 18F-fluoroethyltyrosine
Fatty acid 11C-palmitic acid
TCAa cycle 11C-acetic acid
Membrane lipid synthesis 11C-choline
18F-fluorocholine
Nucleoside 18F-FLTb
8F-FHBGc
Ischaemia 18F-fluoromisonidazole
Dopamine 18F-fluorodopa
a TCA: Tricarboxylic acid.
b18F-FLT: 3¢-deoxy-3¢-fluorothymidine.
c18F-FHBG: 9-(4-18F-fluoro-3-hydroxymethylbutyl)-guanine.
Although receptor binding PET agents (Table 5) are the most intensively studied of the agents used, their clinical application was less successful than that of metabolic PET agents.
The number of receptors expressed on cell surfaces or inside cells is limited. As a result, only a limited number of radiopharmaceutical molecules can bind to receptors. This greatly restricts the use of receptor binding radio-pharmaceuticals for imaging receptors.
Another limitation of receptor binding agents is their binding affinity. In general, dissociation constant (Kd) values of nanomolar affinity are required for good receptor imaging. If the affinity of the agent is low, the ratio of bound to free PET ligand concentration would decrease and will subsequently reduce the target to non-target ratio.
For brain receptor imaging agents, lipophilicity and molecular weight are also important factors for penetration into brain tissue. In general, a log P value of 2–4 is recommended for brain receptor binding agents. If the log P value is lower than 2, penetration through the blood–brain barrier will be low. On the other hand, if the log P value is higher than 4, its protein binding would be too high, which would also reduce the brain uptake of the agent. In general, a
TABLE 5. RECEPTOR BINDING PET AGENTS
Receptor PET agent
Dopamine D1 11C-Schring23390
Dopamine D2 11C-FLB457
11C-Raclopride
Dopamine transporter 11C-WIN35428 (b-CFT)
18F-FP-CIT Serotonin transporter 11C-DAS
11C-WAY-100635
18F-MPPF Benzodiazepine receptor 11C-flumazenil
18F-fluoroethylflumazenil
18F-fluoroflumazenil Opioid receptor 11C-1-carfentanil b-amyloid plaque 11C-PIB
Oestrogen receptor 18F-FES
molecular weight of less than 500 daltons is optimal for penetration through the blood–brain barrier.
Although b-amyloid plaque is not a brain receptor, the mechanism of its imaging is the same as that of other receptor agents. Carbon-11-PIB (Pittsburgh Compound B) is a promising PET agent, owing to its excellent imaging properties and the clinical importance of Alzheimer’s disease imaging.
1.8.3. Peptide agents
For peptide PET agents, the following factors are relevant:
(a) The clinical importance of the target peptide receptor. The target receptor should represent a specific cell condition or pathological state.
(b) Small molecular weight is important for rapid blood and non-target tissue clearance, thus producing a high quality image with high target to non-target ratio.
(c) A high affinity to the target receptor is mandatory.
(d) A high specificity to the target receptor is recommended.
(e) No or a low metabolism is required for accurate receptor imaging.
(f) For whole body PET, excretion through the kidneys is preferable to excretion through the hepatobiliary tract.
Peptide PET agents are regarded as the most promising agents for clinical application in the future. Peptides can target numerous different cells (Table 6).
The most successful peptide PET agents are octreotide derivatives. Fluorine-18 and 68Ga are recommended positron emitters for peptide labelling. Carbon-11 is not recommended because of its short half-life and the fact that a period of one or two hours washout is required for peptide imaging.
For clinical introduction of peptide PET agents, the clinical importance of target tissue is the most important factor. The affinity of the peptide to the receptor and the abundance of the receptor are also important for a high target to non-target ratio in the image. The molecular weight of the peptide should be less than 30 kilodaltons for rapid clearance from blood and non-target tissues.
Fluorine-18 is preferred because of its relatively long half-life, and 68Ga is preferred because it is easy to prepare. Gallium-68 is obtained from 68Ge–68Ga generators, which enable PET imaging without operation of a cyclotron and complicated automatic radiopharmaceutical synthesizers.