[^99mTc]Demotate, a new ^99mTc-based [Tyr³]octreotate analogue for the detection of somatostatin receptor-positive tumours: synthesis and preclinical results

Abstract.

Demotate is a new tetraamine-functionalised [Tyr³]octreotate derivative that binds technetium-99m with a high efficiency under mild conditions. The resulting radioligand, [^99mTc]Demotate, forms in a high purity and is stable for at least 6 h after labelling. The affinity of the unlabelled peptide for somatostatin receptors is high (IC₅₀=0.13 nM) and comparable to that of [Tyr³]octreotate or [Tyr³]octreotide, as demonstrated by competition binding experiments in rat brain cortex or AR42J cell membrane preparations. An equally very high affinity (K _d=0.07 nM) was exhibited by [^99mTc/^99gTc]Demotate during saturation binding experiments using rat brain cortex membrane homogenates. The radioligand resisted hydrolytic degradation in mouse plasma and was excreted intact in mouse urine. In vivo, [^99mTc]Demotate cleared very rapidly from non-target tissues into the bladder via the kidneys, while radioactivity uptake in target organs was very high. In mice bearing the experimental AR42J tumour, [^99mTc]Demotate demonstrated a very high tumour uptake at 1 h p.i. (25%ID/g) that remained high (20%ID/g) at 4 h p.i. This uptake could be effectively blocked by co-injection of a high dose of [Tyr³]octreotate together with the radioligand. High-quality planar and single-photon emission tomographic images were acquired 1 h after injection of [^99mTc]Demotate in tumour-bearing mice, illustrating the excellent properties of this agent for somatostatin receptor tumour imaging.