The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis is a major challenge that must be overcome, as it can result in an impractically short in vivo biological half-life and a subsequently poor bioavailability when used in imaging and therapeutic applications. Consequently, many biologically and pharmacologically interesting peptide-based drugs may never see application. A potential way to overcome this is using peptide analogues designed to mimic the pharmacophore of a native peptide while also containing unnatural modifications that act to maintain or improve the pharmacological properties. This review explores strategies that have been developed to increase the metabolic stability of peptide-based pharmaceuticals. It includes modifications of the C- and/or N-termini, introduction of d- or other unnatural amino acids, backbone modification, PEGylation and alkyl chain incorporation, cyclization and peptide bond substitution, and where those strategies have been, or could be, applied to PET peptide-based radiopharmaceuticals.

The importance of the sulfur-fluorine bond is starting to increase in modern medicinal chemistry literature. This is due to a better understanding of the stability and reactivity of this moiety depending on the various oxidation states of sulfur. Furthermore, several commercial reagents used for mild and selective fluorination of organic molecules are based on the known reactivity of S-F groups. In this review, we will show how these examples are translating into the 18F field, both for use as stable tags in finished radiopharmaceuticals and as mildly reactive fluoride-relay intermediates. Finally, we also discuss current opportunities where examples of non-radioactive S-F applications/chemistry may be translated into future 18F radiochemistry applications.

Molecules that feature a sulfonyl fluoride (SO2F) moiety have been gaining increasing interest due to their unique reactivity and potential applications in synthetic chemistry, medicinal chemistry, and other biological uses. A particular interest is towards 18F-radiochemistry where sulfonyl fluorides can be used as a method to radiolabel biomolecules or can be used as radiofluoride relay reagents that facilitate radiolabeling of other molecules. The low metabolic stability of sulfonyl fluoride S–F bonds, however, presents an issue and limits the applicability of sulfonyl fluorides. The aim of this work was to increase understanding of what features contribute to the metabolic instability of the S–F bond in model aryl sulfonyl fluorides and identify approaches to increasing sulfonyl fluoride stability for 18F-radiochemistry and other medicinal, synthetic chemistry and biological applications. To undertake this, 14 model aryl sulfonyl fluorides compounds with varying functional groups and substitution patterns were investigated, and their stabilities were examined in various media, including phosphate-buffered saline and rat serum as a model for biological conditions. The results indicate that both electronic and steric factors affect the stability of the S–F bond, with the 2,4,6-trisubstituted model aryl sulfonyl fluorides examined displaying the highest in vitro metabolic stability.

The one-pot reaction of 2,6-bis(diphenylmethyl)-4-methoxyaniline with tert-butylnitrite, BTEAC and DABSO in the presence of CuCl2 provided an unexpected 3H-indazole product 8. The structure of the compound was determined by HRMS, IR, NMR and further confirmed by single crystal X-ray crystallography. The compound crystallises in the triclinic P-1 space group, with unit cell parameters a = 9.2107 (4), b = 10.0413 (5), c = 14.4363 (6) Å, α = 78.183 (2), β = 87.625 (2), γ = 71.975 (2)°. The formation of 8 proceeded through a facile intramolecular [2 + 3] cycloaddition of the diazo intermediate 9. The molecules of 8 are organised by edge–face Ar–H···π, face–face π···π, and bifurcated OCH2–H···N interactions. In addition to these, there are Ar–H···H–Ar close contacts, (edge–edge and surrounding inversion centres) arranged as infinite tapes along the a direction.