Homochiral Radioligands for PET: Aspects of Asymmetric Synthesis, Analysis and Behaviour In Vivo

Positron emission tomography (PET) enables strong binding site-radioligand interactions to be studied in vivo. This capability may be exploited to gain new insights into changes in the distribution, density, affinity and occupation of enzymes and neurotransmitter receptors in relation to the progress of disease, or to investigate the action of novel therapeutics with regard to their site(s) of action, effective dose and duration of action. The strong binding site-radioligand interactions tend to be enantioselective (see Lehmann, 1986) and if so demand the use of a homochiral radioligand, usually the more potent enantiomer (the eutomer). The reasons may be summarised as follows: i) to avoid the confusing effects of any differential distribution, metabolism, protein binding or pharmacokinetics in the enantiomers of a racemic radioligand. For reviews of such effects in pharmacology, see Simonyi et al. (1986), Testa (1986) and Walle and Walle (1986). ii) to achieve optimal signal-to-noise ratio (e.g. specific/nonspecific radioligand binding) by avoiding contributions to non-specific binding by the less potent enantiomer (the distomer). iii) to obtain kinetic data that can be modelled mathematically to provide meaningful quantitative measurements on binding site populations (e.g. binding potential, KD or Bmax values). For relevant pharmacokinetic discussion see Ariens (1986) and references therein. iv) to avoid unnecessary radiation exposure from the distomer.