In this short review we describe recent methods and novel trends for the introduction of fluorine-18 into molecules which in turn are intended to serve as imaging agents for the in vivo imaging modality positron emission tomography (PET). These 18F-labeling schemes are based on enzymatic fluorination, the use of ionic liquids, protic solvents acting as catalysts, application of “click chemistry”, thiol-reactive labeling agents for peptide and protein labeling and the most recent introduction of “non-classical” radiochemistry based on organo-phosphorous, organo-boron and organo-silicon radiochemistry. The latter approach for the first time introduced an 18F-chemistry characterized by high selectivity and unique efficiency making complicated work-up procedures obsolete.

Today the term “click chemistry” is often used equivalent with the copper-catalyzed 1,3-dipolar Huisgen cycloaddition. Originally, the concept was introduced in 2001 to describe reactions fulfilling a set of criteria that are most useful for chemical syntheses in drug research. In radiopharmaceutical chemistry where short lived radioisotopes are introduced into various different substance classes for in vivo imaging of biochemical processes, the expanding field of radioactive bioconjugation has become predominant. Labeled biomolecules such as peptides, proteins and oligonucleotides generated via bioconjugation of chelators for radiometal introduction as well as novel valuable secondary precursors for 18F labeling have enriched the growing field of molecular imaging substantially. When introducing radioactive nuclides with a very short half-life into biomolecules, some of the typical criteria defined by click-chemistry are more crucial than others. Time is always the most important issue, whereas avoiding the formation of by-products that have to be removed without chromatography is of minor importance. The short-lived radionuclide 11C for example has a physical half-life of only 20 min so that the labeling procedure cannot exceed 40-60 minutes (2-3 half-lifes). In this contribution, we outline reactions and molecules which meet the requirements of click chemistry reactions and are suitable for radiosyntheses of short lived SPECT (99mTc: t1/2 = 6 h, 111In: t1/2 = 2.81 d) and PET (11C: t1/2 = 20.3 min to 64Cu: t1/2 = 12.7 h) radiotracers for in vivo imaging of biological processes and review the contributions in the field of radiochemical “click-reactions” - 1,3-dipolar Huisgen cycloadditions and beyond.

Molecular imaging—and especially Positron Emission Tomography (PET)—is of increasing importance for the diagnosis of various diseases and thus is experiencing increasing dissemination. Consequently, there is a growing demand for appropriate PET tracers which allow for a specific accumulation in the target structure as well as its visualization and exhibit decay characteristics matching their in vivo pharmacokinetics. To meet this demand, the development of new targeting vectors as well as the use of uncommon radionuclides becomes increasingly important. Uncommon nuclides in this regard enable the utilization of various selectively accumulating bioactive molecules such as peptides, antibodies, their fragments, other proteins and artificial structures for PET imaging in personalized medicine. Among these radionuclides, ⁸⁹Zr (t_1/2 = 3.27 days and mean E_β+ = 0.389 MeV) has attracted increasing attention within the last years due to its favorably long half-life, which enables imaging at late time-points, being especially favorable in case of slowly-accumulating targeting vectors. This review outlines the recent developments in the field of ⁸⁹Zr-labeled bioactive molecules, their potential and application in PET imaging and beyond, as well as remaining challenges.

Radiolabeled peptides for tumor imaging with PET that can be produced with kits are currently in the spotlight of radiopharmacy and nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, ⁶⁸Ga and ¹⁸F stand out because of the ease of radionuclide introduction (e.g., ⁶⁸Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring the ¹⁸F isotope). The in vivo properties of good manufacturing practice–compliant, newly developed kitlike-producible ¹⁸F-SiFA– and ¹⁸F-SiFAlin– (SiFA = silicon-fluoride acceptor) modified TATE derivatives were compared with the current clinical gold standard ⁶⁸Ga-DOTATATE for high-quality imaging of somatostatin receptor–bearing tumors. Methods: SiFA- and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried ¹⁸F and purified via a C18 cartridge (radiochemical yield 49.8% ± 5.9% within 20–25 min) without high-performance liquid chromatography purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution and in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles, and the results were compared with those of the current clinical gold standard ⁶⁸Ga-DOTATATE. Results: Synthetically easily accessible ¹⁸F-labeled silicon-fluoride acceptor–modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor–positive tumor cells (1.88–14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor standardized uptake values in PET/CT imaging than ⁶⁸Ga-DOTATATE in vivo. The radioactivity uptake in nontumor tissue was higher than for ⁶⁸Ga-DOTATATE. Conclusion: The introduction of the novel SiFA building block SiFAlin and of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumor-to-background ratios although lower than those observed with ⁶⁸Ga-DOTATATE. As further advantage, the SiFA methodology enables a kitlike labeling procedure for ¹⁸F-labeled peptides advantageous for routine clinical application.