Selecting PET radiopharmaceutical


The kinetics of a radiopharmaceutical must be related predominantly to the process of concern. It should have no label-carrying metabolites that can accumulate in tissue.

Non-specific binding to other proteins and lipids should be low to enable sufficient signal-to-background ratio. Relatively high lipophilicity of the radiotracer may be required to ensure high delivery to the tissue (due to easier membrane permeability and increased circulation time). Unfortunately lipophilicity may also increase the non-specific uptake.

Radiopharmaceutical, especially when aimed for CNS studies, should not be a strong substrate for efflux transporters (P-gp, MDR, BCRP).

Molar activity

To obtain good counting statistics without violating the criterion of minimal mass effect due to the radiotracer, the molar activity (specific activity) should be high enough.

This is especially crucial with the neuroreceptor-binding ligands: the tissue concentration of neuroreceptors in brain is only in the range of picomoles per gram, and the radioligand molecules should not occupy more than 1 to 5% of these receptor sites. Upper mass dose limit should be estimated as part of validation of every receptor ligand (Madsen et al., 2011).

Time window of PET

Turnover time of the tracer in tissue must be within the time window of the PET technique and the radioactivity decay time of the radionuclide used as label.

PET has high sensitivity to noise, which means a relatively long collection time for each scan (frame). This limits the temporal sampling frequency of the tracer kinetic data, and excludes PET from measuring pools or processes that have turnover times much shorter than a few seconds.

The commonly used positron emitters have rather short half-lives. This imposes an upper limit on the pool turnover times that PET can measure. Considering the radiation dose to the subject, the half-life should not be longer than is required for high-quality measurements.

Chemical analogues

Chemical analogues are compounds that have chemical structures similar to the natural substrates, except that at some key positions the molecules are modified. For the transport processes and reactions that are not critically dependent on the modified molecular positions, the analogues will behave similarly to their natural substrates. However, for those reaction steps that are specific to the modified positions, the analogues will have completely different characteristics than the natural substrates, or will not be substrates for the reactions any more. Chemical analogues are used to isolate selected portions of complex biochemical reaction sequences.

An example of an analogue used in PET is 2-[18F]fluoro-2-deoxyglucose (FDG). FDG is transported in tissue and phosphorylated by hexokinase in the same manner as glucose, but because the hydroxyl group on the number 2 carbon has been replaced by 18F, FDG-6-phosphate is not a substrate for the next reaction step in the glycolytic pathway, or for glycogen synthesis or for pentose shunt, and is trapped in most tissues. Therefore it is an optimal tracer for measuring the metabolic rate of glucose.

Another example is [11C]-Methyl-D-glucose, which is transported into tissue like glucose and FDG, but is not metabolized. Therefore it is an optimal tracer for measuring the amount of glucose transporters and intracellular glucose concentration.

Natural substrates

Unlike the analogue tracer, labeled natural substrates usually cannot be used to isolate specific reaction steps. Description of their kinetics would require more complicated models.

For example, the label of [11C]glucose goes through many reaction steps in the glycolytic pathway before it is cleaved away as [11C]CO2, and is soon found in other labeled compounds, such as lactate and urea in blood and tissue. From [1-11C]palmitate the label is cleaved away as [11C]CO2 in the first beta-oxidation cycle. Severe modelling problems may emerge from [11C]CO2 producing tracers: in fact, [11C]CO2 inhalation studies have been done to measure tissue pH.

Advantage with natural substrates is that there is no need for correction terms for different affinities for transporters and enzymes, like "lumped constant" for FDG.

See also:


Eckelman WC. The application of receptor theory to receptor-binding and enzyme-binding oncologic radiopharmaceuticals. Nucl Med Biol. 1994; 21(5): 759-769. doi: 10.1016/0969-8051(94)90047-7.

Goodpaster BR, Bertoldo A, Ng JM, Azuma K, Pencek RR, Kelley C, Price JC, Cobelli C, Kelley DE. Interactions among glucose delivery, transport, and phosphorylation that underlie skeletal muscle insulin resistance in obesity and type 2 diabetes: studies with dynamic PET imaging. Diabetes 2014; 63: 1058-1069. doi: 10.2337/db13-1249.

Huang SC., Carson R.E., Phelps M.E. (1983): Tracer Kinetic Modeling in Positron Computed Tomography. In: Lambrecht R.M., Rescigno A. (eds.) Tracer Kinetics and Physiologic Modeling. Lecture Notes in Biomathematics, vol 48. Springer, Berlin, Heidelberg. doi: 10.1007/978-3-642-50036-7_6.

Jones T. The imaging science of positron emission tomography. Eur J Nucl Med. 1996; 23: 807-813. doi: 10.1007/bf00843711.

Lewis JS, Windhorst AD, Zeglis BM (eds.): Radiopharmaceutical Chemistry. Springer, 2019. doi: 10.1007/978-3-319-98947-1.

McCluskey SP, Plisson C, Rabiner EA, Howes O. Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development. Eur J Nucl Med Mol Imaging 2020; 47: 451-489. doi: 10.1007/s00259-019-04488-0.

Mukherjee J, Shi B, Narayanan TK, Christian BT, Zhi-Ying Y (2004): Radiopharmaceuticals for imaging the brain. In: Emission Tomography: The Fundamentals of PET and SPECT. (Eds: Wermick MN, Aarsvold JN). Elsevier Inc., pp 89-101.

Shegani A, Kealey S, Luzi F, Basagni F, Machado JDM, Ekici SD, Ferocino A, Gee AD, Bongarzone S. Radiosynthesis, preclinical, and clinical positron emission tomography studies of carbon-11 labeled endogenous and natural exogenous compounds. Chem Rev. 2023; 123(1): 105-229. doi: 10.1021/acs.chemrev.2c00398.

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Updated at: 2023-01-20
Created at: 2011-11-22
Written by: Vesa Oikonen