Advances in F-18 radiopharmaceutical chemistry

Full text: Concomitant with the increasing variety of biochemical principles applied for molecular imaging and hence with the growing number of compound classes used, there is a permanent demand for new or adapted methods of labelling. Besides carbon-11 (T1/2 20.4 min), fluorine-18 (T1/2 109.7 min) is still the most commonly employed positron-emitter in radiopharmaceuticals for PET. Not as much for tracers of metabolic substrates but as, e.g., for ligands of neurotransmission or for enzyme inhibitors a high specific activity is crucial and demanding. Also for application in small animal PET-devices significant activity levels have to be attained in minimum volumes without pharmacological mass interferences. In spite of recent attempts to achieve this goal for electrophilic 18F-fluorination by means of electrochemistry or via radiation induced chemistry, a proper realization was hampered by low radiochemical yields. Still today, nucleophilic substitution with n.c.a. [18F]fluoride appears to be the only practical way to achieve high specific activity products. While this is generally easy to attain with aliphatic or aromatic molecules activated for nucleophilic exchange of suitable leaving groups, it is still a problem with electron-rich arenes, especially if they are of complex structure. Enhancement of the 18F-labelling possibilities was obtained by the use of activated aromatic heterocylic compounds such as pyridines and recently 1,3-thiazoles as well as by the introduction of aryliodonium moieties as nucleofugic groups. Especially the thienyl-iodonium leaving group offers possibilities for direct n.c.a. radiofluorination of electron rich arenes. With complex molecules to be labelled, build-up reactions cannot be avoided. But again the recent development of 18F-labelled synthons like fluorophenol, fluoroaniline or fluorobromo( iodo)benzene, in part prepared by the above mentioned methods, facilitates their preparation on a n.c.a. scale. Especially fluorohalobenzenes offer versatile possibilities via Grignard-reactions and lithium intermediates or in Pd-mediated coupling reactions. Similarly, new or improved prosthetic groups meet the fast-growing interest in 18F-labelling of peptides and oligomers. Further technical improvements in preparation methodologies help to fulfil the demands of increased clinical study frequencies. These newer radiofluorination procedures will be exemplified with relevant radiotracers for various areas of application. (author)