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Biologics-based radiopharmaceuticals, i.e., biological components, including peptides, proteins, polysaccharides, and nucleic acids and their combinations, are increasingly introduced in preclinical and clinical molecular imaging procedures. Synthetically prepared, extracted from natural sources, selected from biological processes, or products of cutting-edge biotechnologies, they all together represent an almost unlimited pool of radiopharmaceutical candidates. No other class of molecules offers the range of chemical diversity that biologics possess. This rich nature's toolkit uncovers a wide range of functions or dysfunctions of the human body with often incomparable potency. The downside is nevertheless that their particular chemical structures and the diversity of chemical functions they bear imply specific radiolabeling approaches. This book chapter will review the existing methods to radiolabel biologics with fluorine-18, with a particular focus on the most recent bioorthogonal conjugation approaches and strategies derived from chemical biology. An outlook to the direct in vivo labeling possibilities will also be given.

Publisher Summary Positron emission tomography (PET) is a high-resolution, sensitive, functional-imaging technique in nuclear medicine that permits repeated, non-invasive assessment, and quantification of specific biological and pharmacological processes at the molecular level in humans and animals. It is the most advanced technology currently available for studying in vivo molecular interactions in terms of distribution, pharmacokinetics, and pharmacodynamics. Molecular PET imaging requires the preparation of a positron-emitting radiolabeled probe or radiotracer. For this purpose, fluorine-18 is becoming increasingly the radionuclide of choice not only due to its adequate physical and nuclear characteristics but also due to the successful use in clinical oncology of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), currently the most widely used PET radiopharmaceutical and manifestly a motor behind the growing availability and interest for this positron emitter in radiopharmaceutical chemistry. This chapter addresses this complex interdisciplinary and rapidly growing field from a radiochemist point of view, focusing on the synthesis of fluorine-18-labelled radiopharmaceuticals. The successful use in clinical oncology of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), currently the most widely used PET radiopharmaceutical, is manifestly also the motor behind the growing availability and interest for this positron emitter in radiopharmaceutical chemistry. The use of fluorine-18, however, presents some drawbacks in particular the limited options in labeling strategies. The synthesis of complex structures labeled with fluorine-18 remains a challenge but undoubtedly, fluorine-18 is already, and will continue to be, a royal gateway to success in molecular imaging with PET.