Asymmetric Synthesis of Carbon-11 Labelled α-Amino Acids for PET

Alexander      Popkov; Philip   H.   Elsinga

Abstract

For PET applications in oncological and neurological diagnostics, amino acids have been studied both clinically and pre-clinically during the last 35 years. Nowadays two applications of labelled amino acids for visualisation of tumours attract the main attention: [¹¹C] or [¹⁸F]amino acids as substrates of specific membrane transport systems or in vivo measurement of protein synthesis rate. In this review we focussed on ¹¹C-labelled amino acids, since synthetic approaches to [¹⁸F]amino acids have been extensively reviewed in the literature. Most of optically pure ¹¹C-labelled amino acids (except [¹¹C]methionine) have been prepared via low-yield non-reliable synthetic procedures. Low availability hampers their evaluation as biological probes. The first synthesis of racemic [¹¹C]lactic acid as an [¹¹C]amino acid precursor was published in 1941. It took more than thirty years to develop the first synthesis of a racemic [¹¹C]amino acid, it was published in 1973. Early examples of asymmetric synthesis of [¹¹C]amino acids led to relatively low enantiomeric excess, up to 82%. Amino acids synthons developed by groups led by Oppolzer, Seebach, Belokon and Horwell allowed highly stereospecific preparation of [¹¹C]amino acids. Enzymatic and biotechnological approaches, catalytic [¹¹C]alkylation of achiral glycine synthons or catalytic hydrogenation of [¹¹C]precursors have not resulted in any practically useful syntheses yet. The importance for PET using new α-substituted amino acids is briefly discussed.