Development of novel peptide based radiopharmaceuticals for in vivo receptor associated tumor diagnosis and therapy

• Research unit: EU RFP
• Project number: 96.0447-1

Key words (English)

Neurotensin; bombesin; Tc-99m;Re-188; radionuklide labelling;

Alternative project number (English)

EU project number: BMH4-CT98-3198

Research programs (English)

EU-programme: 4. Frame Research Programme - 4.2 Agriculture and agroindustry

Short description (English)

See abstract

Further information (English)

Full name of research-institution/enterprise:
Paul Scherrer Institut PSI
Zentrum für radiopharmazeutische Wissenschaft

Partners and International Organizations (English)

Coordinetor: Forschungszentrum Rossendorf e.V. (D)

Abstract (English)

Neurotensin (NT) and bombesin (BBN) are neuropeptides which are considered to be useful for tumour diagnosis (labelled with Tc-99m) and tumour therapy (labelled with Re-188) in nuclear medicine. So far the in vitro properties with HT-29 or PC-3 cells and in vivo behaviour in nude mice with tumour xenografts are investigated. The Ca-influx measurements showed that all the NT and BBN analogues are agonists.
For both peptides and both nuclides the metall-tricarbonyl complex was used for labelling.
1. Neurotensin
Several analogues of NT 8-13 ((NaHis)Ac-Arg-Arg-Pro-Tyr-Ile-Leu) labelled with Tc-99m were investigated. The non-stabilised NT analogues are quickly degraded in human plasma and show rather poor uptake in tumour xenografts in nude mice. The main increase of the stability was found, when Ile was replaced by Tle. The reduction of the Arg-Arg peptide bond to an amine led only to a marginal increase of the stability, however the combination of both reduction of this bond and introduction of Tle gave a product (NT-XI) which resisted virtually completely enzymatic degradation. The tumour uptake increased parallel with the increase of the plasma stability. Other analogues were synthesised and tested, among them one with the N-methyl-arginine instead of the Arg-8 which showed the highest tumour uptake and the best tumour to non-target-tissue uptake ratios in the nude mouse model. The permission from the national office of health (BAG) has recently been obtained to study Tc-99m-NT-XI in patients, but the patient study (A.Bischof Delaloye, Lausanne) will be performed after the termination of funding.
We have introduced now the Re-188 for labelling the NT analogues and in the in vitro tests not found significant differences compared to Tc-99m. However, even slight differences might influence the selection of the NT analogue for the therapy of pancreatic tumours, and thus, further tests have to be done before we can envisage a patient application.
2. Bombesin
D.Tourwé, Brussels, solved only recently the problem of linking the (NaHis)Ac to Bombesin7-14 (Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2). In contrast to the PADA (the bifunctional chelator picoline-amine-N,N-diacetic acid) derivative this new analogue allowed the much easier direct labelling approach. Both compounds have been characterised with several methods in vitro and in a nude mouse model in vivo. Blockade studies showed a specific uptake and receptor binding. However, the short half life of less than one hour in plasma explains the rather low uptake. Introduction of stabilised forms led to a reduced affinity to the GRP receptor.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 96.0447-1