[^123/131I]Iodometomidate as a radioligand for functional diagnosis of adrenal disease: synthesis, structural requirements and biodistribution

Metomidate [(R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid methyl ester] (MTO, 1, Fig. 1) is a potent and selective inhibitor of the cytochrome P-450 enzyme system in the adrenal cortex. Labelled in the 4-position with radioiodine, (R)-4-[I-13]fliodometomidate, 2, [I-131]IMTO has been evaluated by in-vitro studies and also ex-vivo in rats. [I-131]IMTO was synthesized by oxidative radioiododestannylation using a suitable precursor which was prepared by a new stereoselective synthesis. Optimization of the labelling reaction was performed by systematic variation of the most important reaction parameters. Under optimum reaction conditions, a labelling yield of 95% was obtained. In-vitro-stability of the tracer was studied over 8 days, indicating slow deiodination (0.27%/h). Displacement studies using [I-131]IMTO and rat adrenal membranes revealed the structural requirements for high affinity binding, namely an intact ester group and (R)-configuration of the radioligand. Pharmacokinetic studies in rats showed fast accumulation of [I-131]IMTO in the adrenals (approx. 10% ID/g tissue) with an activity plateau for 2 hours. Metabolic degradation was indicated by a steady increase of renal activity up to 4 hours post injection. Based on target to non-target ratios the highest contrast for imaging of the adrenals was observed between 30 and 60 min post injection of [I-131]IMTO. We conclude that SPECT using [I-123]IMTO will be a promising method for the characterization of adrenal incidentalomas.