Radiotracers, synthesis

Allard, M., Fouquef E., James, D., Szlosek-Pinaud, M. 2008. State of art in C labelled radiotracer synthesis. Curr. Med. Chem. 15 235-277. 

Fowler, J S, Wolf, A P The Synthesis of Carbon-II, Fluorine 18 and Nitrogen 13 Labeled Radiotracers for Biomedical Applications, Mono graph NAS-NS-3601, Technical Information Center, U S Department of Energy... 

This synthetic approach is attractive because the trialkyltin group can be removed rapidly and cleanly under mild reaction conditions and because the expensive label, which invariably has a short half-life, is not added until the last step in the synthesis. Because of these advantages, this synthetic approach has been widely used by several research groups to prepare radiohalogenated labelled hormones, neurohormones, neurotransmitter receptors, etc. for radiotracer and therepeutic uses123. 

The resulting device has demonstrated both FDG and FLT labelling at yields of 98% and 90%, respectively, in 100 s compared to typical macro-scale labelling of 65% in 45 min for FDG and 30% in 90 min for FLT. The use of acetonitrile, DMSO and HC1 have shown no degrading effect on the system. Extremely efficient labelling illustrates the effectiveness of flow-based micro-reactors for PET biomarker synthesis. Multiple biomarkers can be produced in 1-2 min, while using only micro-litres of precursor and can revolutionise the production of radiotracers. Small reaction volumes, improved yields, and the ability to synthesise small quantities of a variety of new compounds will allow preclinical and clinical evaluation of new PET agents with potential for clinical utilisation. 

Radiation protection and automation of synthetic procedures have to be carefully considered when planning synthesis of F-radiotracers. They require the simplification of all the manipulations or transfers and this point will not be discussed here. 

Scheme 50 presents some recent examples of direct nucleophilic exchanges F/TsO compared to F/MsO or F/TfO in the synthesis of radiotracers directly usable for PET studies [209,210] and chosen for their structural diversity. 

An example of fluorination of a po/yfluoroalkene with [ F]p2 is the synthesis of [ F]EF5 (Scheme 15), a radiotracer used to assess tissue hypoxia. The radiochemical yield was over 10% [90]. 

K. Hamacher, Synthesis of n.c.a. cis- and trans-4-[ F]fluoro-L-proline, radiotracers for PET-investigation of disordered matrix protein synthesis, J. Label. Compds Radiopharm. 42 (1999) 1135-1144. 

The synthesis of a new precursor of 5-IA-85380, a specific radiotracer for a4(32 nicotinic acetylcholine receptors, that is, (A)-5-trimethylstannyl-3-(2-azetidinylmethoxy)pyridine 109, has been accomplished in six steps and 62% overall yield by functional group transformations of the carboxyl group in (A)-azetidine-2-carboxylic acid 23 (Scheme 22) <2004TL3607>. 

To monitor tumor response to capecitabine therapy noninvasively, Zheng and co-workers, from the Indiana University School of Medicine, developed the synthesis of the fluorine- 18-labeled capecitabine as a potential radiotracer for positron emission tomography (PET) imaging of tumors.28 Cytosine (20) was nitrated at the C-5 position with nitric acid in concentrated sulfuric acid at 85°C, followed by neutralization to provide 5-nitrocytosine (27) in moderate yield. This nitro pyrimidine was then carried through the glycosylation and carbamate formation steps, as shown in the Scheme below, to provide the 6/s-protected 5-nitro cytidine 28 in 47% for the three-step process. Precursor 28 was then labeled by nucleophilic substitution with a complex of 18F-labeled potassium fluoride with cryptand Kryptofix 222 in DMSO at 150 °C to provide the fluorine-18-labe led adduct. This intermediate was not isolated, but semi-purified and deprotected with aqueous NaOH in methanol to provide [l8F]-capecitabine in 20-30% radiochemical yield for the 3-mg-scale process. The synthesis time for fluorine-18 labeled capecitabine (including HPLC purification) from end of bombardment to produce KI8F to the final formulation of [18F]-1 for in vivo studies was 60-70 min. 

PET has already been applied to a wide number of drugs to demonstrate activity in vivo from standard chemotherapy such as 5-fluorouracil (5-FU). The pharmacokinetics of 5-FU has been successfully investigated using radiotracers, and is the most common anti-cancer drug imaged with PET (Kissel). This is due to the ease of chemical synthesis of 18F-fluorouracil... 

Many biologically active substances and neuroleptic drugs have a seven-membered ring in their structure. Benzodizapines of extremely high specific activity used in receptor binding studies are isotopically labelled by synthesis. The specific activities of compounds 137-150 are sufficiently high for in vitro metabolic and radiotracer studies. 

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