P.E.T. Radiopharmaceuticals Via Reductive Carboxylation

Abstract

Positron Emission Tomography (PET) is a powerful imaging diagnostic tool which uniquely provides qualitative and quantitative measurement of metabolic processes in vivo in normal and pathological tissue via application of appropriate radiotracers. Recently, there has been great interest in the development of fast and efficient new synthetic methodologies for positron emitting radiolabeled pharmaceuticals which can be used as tracers for P.E.T. studies. In the last decade, a variety of N-[¹¹C] labeled radiopharmaceuticals^1–2 have been synthesized via methylation of the appropriate desmethyl precursors with [¹¹C]CH₃I or reductive methylation with [¹¹C]HCHO/NaBH₃CN. In principle, both of these reagents [¹¹C]CH₃I or [¹¹C]HCHO have been prepared from the more readily available [¹¹C]CO₂ via reduction to [¹¹C]CH₃OH, followed by iodination or oxidation as illustrated in Scheme-1. Further examination of the N-[¹¹C] radiopharmaceuticals reveals that these bioactive molecules can be easily prepared directly from [¹¹C] carbon dioxide under appropriate conditions. We have, therefore, investigated the use of [¹¹C]CO₂ as a radiolabeled precursor in the preparation of a variety of [¹¹C] labeled compounds. In order to develop new synthetic methodologies for direct incorporation of [¹¹C]CO₂ into bioactive molecules, synthesis should be short and efficient and should be complete within three half-lives of the radioisotope. In general, literature synthetic procedures³ using [¹²C] or [¹⁴C]CO₂ are not applicable for the synthesis of [¹¹C] labeled radiopharmaceuticals because of the short 20.4 min half-life of the [¹¹C] isotope. Hence, either extremely modified or entirely new procedures are desirable. A general reaction of [¹¹C]CO₂ with organometallics has been widely used for the preparation of [¹¹C] carboxylic acid derivatives.