Review
Radiolabelled proteins for positron emission tomography: Pros and cons of labelling methods

https://doi.org/10.1016/j.bbagen.2010.02.002Get rights and content

Abstract

Background

Dynamic biomedical research is currently yielding a wealth of information about disease-associated molecular alterations on cell surfaces and in the extracellular space. The ability to visualize and quantify these alterations in vivo could provide important diagnostic information and be used to guide individually-optimized therapy. Biotechnology can provide proteinaceous molecular probes with highly specific target recognitions. Suitably labelled, these may be used as tracers for radionuclide-based imaging of molecular disease signatures. If the labels are positron-emitting radionuclides, the superior resolution, sensitivity and quantification capability of positron emission tomography (PET) can be exploited.

Scope of review

This article discusses different approaches to labelling proteins with positron-emitting nuclides with suggestions made depending on the biological features of the tracers.

Major conclusions

Factors such as matching biological and physical half-lives, availability of the nuclide, labelling yields, and influences of labelling on targeting properties (affinity, charge and lipophilicity, cellular processing and retention of catabolites) should be considered when selecting a labelling strategy for each proteinaceous tracer.

General significance

The labelling strategy used can make all the difference between success and failure in a tracer application. This review emphasises chemical, biological and pharmacological considerations in labelling proteins with positron-emitting radionuclides.

Section snippets

Applications of polypeptides as imaging probes

Interest in the use of radiolabelled proteins and peptides both as imaging tools during preclinical development and as clinical diagnostics and therapeutics has been increasing during the last decade. This is to a large extent due to the success of genomics and proteomics in identifying disease-related aberrations in the structure or expression levels of cellular proteins. This basic knowledge is rapidly being translated into the development of specific therapeutics that act by the molecular

Positron emission tomography as the imaging technique

PET is an in vivo tomographic imaging technique. It is based on the detection of anti-parallel 511 keV photons emitted during the annihilation of positrons with electrons. The positrons come from the decay of positron-emitting nuclides. If those radionuclides are appropriately attached to a molecule of interest, PET measurements of the concentrations of radioactivity throughout a body can be used to make deductions about the molecule's distribution, metabolism, elimination, ability to interact

Some general considerations on the selection of a label

Depending on the intended application of the labelled biomolecule, the requirements made on the radiolabelling method will differ substantially:

  • For pharmacokinetics studies, it is essential that the distribution of the radioactivity should reflect as accurately as possible that of the non-labelled molecule. Therefore the label and linker should generally be small and should not appreciably affect the biomolecule's lipophilicity, folding, biological activity, etc. The tracing ability of the

Influence of the labelling method on the biodistribution and targeting properties of a tracer

It is important to remember that neither PET nor any of the nuclide-based in vivo imaging techniques track a molecule's localization in a target or even the biodistribution of a labelled molecule. PET visualizes (and provides quantitative information about) the distribution of a radioactivity concentration in vivo. The radioactivity may be the tracer bound to its target, the non-bound tracer, radiometabolites or a combination of these. If the goal of the experiment is to visualize and quantify

Experiences in labelling proteins with positron-emitting radionuclides

The development and clinical use of PET have mainly been based on the use of short-lived (half-lives of 2–110 min) nuclides 15O, 13N, 11C and 18F. The majority of strategies for radiolabelling proteins for PET have been performed with the more long-lived nuclides, primarily because it has been more appropriate for probes expected to stay in circulation for long times and, practically, because it is much easier to not have to work so “on-line” with a cyclotron facility by using the oxidative

Acknowledgements

Vladimir Tolmachev expresses his gratitude to the Swedish Medical Research Council (Vetenskapsrådet) for supporting his research in medical imaging and Sharon Stone-Elander gratefully acknowledges funding for radiolabelling protein probes for PET from the Swedish Medical Research Council (K2009-53X-20033-04-2) and Swedish Agency for Innovation Systems (Vinnova; 2009-00179).

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