Development of High Affinity Pan-somastotin Receptor Ligands and their Labelling with Radionuclides for a Broader Application in Tumor Diagnosis and Internal Radiotherapy

• Research unit: COST
• Project number: C00.0091

Key words (English)

Somatostatin receptors; tumor targeting; internal radiotherapy; neuroendocrine tumors

Research programs (English)

COST-Action B12 - Biological Functions by Radiotracers

Short description (English)

See abstract

Partners and International Organizations (English)

A, B, CZ, DK, FIN, F, D, GR, H, I, NL, N, PL; P, SI, E, S, CH, GB

Abstract (English)

In the last intermediate report we referred to the synthesis of DOTA-[1-Nal]3-octreotide (DOTA-NOC) showing an improved sstr affinity profile and very good results in internalization and biodistribution. This compound is now in clinical trials and shows promising localization in thyroid tumors. The work along these lines continued and new conjugates have been developed: DOTA-[BzThi]3-octreotide (sstr2 aff = 3.7nM; sstr3 aff = 6.9 nM; sstr5 aff = 6 nM), DOTA-[1-Nal]3-[Thr]8-octreotate (sstr2 aff = 1.6 nM; sstr3 aff = 13 nM; sstr5 aff = 4.3 nM), DOTA-[BzThi]3-[Thr]8-octreotate (sstr2 aff = 1.1 nM; sstr3 aff = 7 nM; sstr5 aff = 4 nM). These new compounds show improved affinity to all three somatostatin receptor subtypes and comparable internalization rate. These favorable data biodistribution is referring not only to the tumor uptake (sstr2), but also to the uptake in other sstr expressing organs, uptake proved by differential blocking studies to be due to the higher affinity to sstr 3 and 5. In the same time the evaluation of the pan-ligand continued. KE108 was designed for labeling with radioiodine; unfortunately KE108 shows no internalization in AR42J tumor cells and low tumor and receptor positive tissue uptake in biodistribution using Lewis rats bearing AR42J tumors. Still, KE108 behaves similarly to SS-28 in inhibiting forskolin-stimulated cAMP accumulation. Not only does it inhibit stimulated cAMP to the same levels as SS-28, but it also does it at similar concentrations. Due to this effect KE108 is likely to have an efficient functional role and may be a useful drug as unlabeled compound, to be developed for long-term therapy in somatostatin receptor- positive tumors as an alternative to the commercially available octreotide or lanreotide. In addition chelator-modified pan-somatostatin peptides were developed also showing high affinity to all receptor subtypes as well as agonistic biological behaviour.

References in databases (English)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C00.0091