Labeling strategies of peptides with ¹⁸F for positron emission tomography

A variety of peptides labeled with the positron emitting radionuclide fluorine-18 have shown promise as tracers for use in positron emission tomography (PET) for the detection of malignancies. Peptides can be produced with a formidable versatility allowing them to target a vast diversity of uniquely expressed or overexpressed receptors associated with pathological conditions. The quantitative nature of PET gives the opportunity to stage and monitor the progress of the disease. The pharmacokinetics of peptides are compatible with the half-life of fluorine-18 (110 min), allowing the generation of high quality PET images within the time frame of 1-3 hours or longer. The production of high energy gamma emitting radiopharmaceuticals puts certain constraints and requirements on the production method. These are to a large extent dictated by the short half-life of the ¹⁸F and the need for appropriate shielding of the operator. For large scale productions, a fully automated production process is a requirement. Compared to low molecular weight fluorine-18 labeled tracers, the production of ¹⁸F-labeled peptides entails specific challenges. As opposed to small organic molecules where direct labeling with no-carrier added 18-fluoride is feasible, peptides do not normally allow for such a direct labeling approach. Therefore, peptides are for all practical purposes labeled by ¹⁸F-prosthetic groups, also called bifunctional labeling agents, making their synthesis relatively complicated. During the last decade, various methodologies have been developed for the introduction of ¹⁸F-fluoride into peptides. The strategies employed for the labeling of peptides with ¹⁸F all represent their own advantages and inconveniences, still some are more flexible than others. In this review, the aim is to provide an overview and discuss the strategies currently used for labeling of peptides with ¹⁸F for PET.