Highlights of PET studies on chiral radiotracers and drugs at Brookhaven

Abstract

We review several PET studies of chiral molecules which have been carried out in our laboratory. In many cases the enantiomers behave differently, reflecting factors such as differential specificity for enzymes and transporters and binding to plasma proteins, as well as selective binding to receptors. These studies demonstrate that PET imaging is a suitable method to investigate the behavior of a chiral drug in the human body and is a powerful tool in drug development. It is important to emphasize the essential and pivotal role that organic synthesis has played in the development of PET during the last quarter century. PET is now an important tool in the neurosciences, cardiology, and oncology and is available in hundreds of institutions worldwide. However, PET is by no means mature in terms of the study of chiral drugs; hundreds of racemic drugs have been developed but only a few have been labeled with positron emitters to study their stereoselectivity. One reason is the complexity of rapid synthesis, including chiral synthesis and chiral purification. New developments in these areas are needed. Although PET is a challenging and expensive technology, it is exquisitely suited to functional and neurochemical studies of the human brain and other organs. Its use in drug research and development holds promise in understanding duration of action and stereoselectivity of drugs and in facilitating drug discovery and the introduction of new drugs into the practice of medicine. Drug Dev. Res.

Competitive demethylation and substitution in N,N,N-trimethylanilinium fluorides

“…Nucleophilic aromatic substitution (S N Ar) is a particularly useful transformation for preparing fluorinated radiotracers for positron emission tomography (PET) [1][2][3][4][5]. Advantages of using nucleophilic reactions for the introduction of [ 18 F] fluoride include the high chemical yields, excellent regioselectivity, and the high radiochemical purity associated with radiotracers prepared by this technique.…”

Fluoride relay: a new concept for the rapid preparation of anhydrous nucleophilic fluoride salts from KF

“…Positron emission tomography (PET) is a powerful in vivo imaging technique for healthcare and drug development. [1][2][3][4] Provided the appropriately labeled radiotracers can be synthesized, the sensitivity of PET makes it useful to study physiology, pharmacokinetics and modes of action of novel and established drugs. 5,6 The most common positron emitting radioisotopes for the labeling of organic molecules are 11 C (t 1/2 = 20.4 min.)…”

28 Radiochemistry

“…The relative advantages and disadvantages of labelling radiopharmaceuticals with specific radionuclides have been discussed in many articles. General aspects concerning the use of cyclotron produced radioisotopes for positron emission tomography have been reviewed, 209 and the roles of carbon-11 and fluorine-18 in nuclear medicine compared, [210][211][212][213] both from the radiochemical and clinical point of view. The use of rhenium-188 labelled biomolecules 214 and the potential of selenium-73 215 and tin-117m 216 have also been crtitcally considered.…”