Synthesis of Radiolabeled Compounds for Clinical Studies

Abstract

During the development of new drugs the candidate’s pharmacokinetic (PK) properties and the absorption, distribution, metabolism, and elimination (ADME) characteristics have to be evaluated first in vitro, then in animals and finally in humans (Caldwell et al. 1995; Roffey et al. 2007). The objectives of human ADME studies are to evaluate mass balance data and, most important, to confirm that the metabolism of the drug is similar to what was described in animal species (Deroubaix and Coquette 2004). In order to keep track of the drug molecules throughout the body and excreta even after their transformation into different metabolites, the administration of radiolabeled drugs is considered essential (Marathe et al. 2004; Dalvie 2000). Usually, ¹⁴C is the label of choice for most drug candidates since it can be introduced into a metabolically stable position in the backbone of the compound, the detection is easy and in case of combustion of samples the produced ¹⁴CO₂ can be nicely absorbed quantitatively (see Scheme B.11-1 ) (Beumer et al. 2006). Generally, ³H-labeled drugs can be prepared more easily and quickly than their ¹⁴C counterparts. On the other hand, the ³H-label is often less biologically stable and it is more difficult to predict its metabolic stability and therefore one always needs to bear in mind the potential risk of the in vivo formation of ³H₂O (Dueker et al. 1998). The latter is highly toxic and can be distributed in the whole body, which makes radioactivity measurement and quantification even in animal studies more difficult. Therefore, ³H-labeled drug candidates are usually administered less frequently to humans and only if the specific activity of the ¹⁴C compound is not sufficiently high enough for the planned investigations, for example, in case of high molecular weight and/or very low dose drugs. For large complex biological molecules, such as proteins, antibodies, etc. a ³H or ¹⁴C-labeling by a total synthesis approach could be extremely difficult or even impossible and hence, an iodination with ¹²⁵I₂ or a ¹²⁵I-precursor could be an alternative approach (Dewanjee 1992). However, the structural changes caused by an additional iodine atom in the molecule have to be considered and both materials (iodinated and non-iodinated) tested for bioequivalence. Other potential radioactive isotopes are ³³P and ³⁵S but compared to ¹⁴C, these isotopes were much less frequently applied for labeling of drug candidates.