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

• Research unit: EU RFP
• Project number: 96.0447-3

Key words (English)

Peptide receptors; neurotensin; bombesin; human cancers; tumor targeting

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

Partners and International Organizations (English)

Coordinator: Forschungszentrum Rossendorf e.V. (D)

Abstract (English)

The high expression of neurotensin (NT) receptors in pancreatic cancer and of gastrin-releasing peptide (GRP) receptors in breast and prostate cancers strongly suggests that these tumors may be targeted in vivo with adequate peptide radioligands. In vitro binding properties of novel peptide-based radiopharmaceuticals were evaluated in human GRP and NT receptor-expressing tumors using in vitro receptor autoradiography with either 125I-Tyr3-NT or 125I-Tyr4-bombesin as radioligands.
In GRP-expressing prostate cancers we found excellent binding affinities for the following chelator-linked bombesin analogs: Demotide 1 [(N4-Bzl-NH-diG-[D-Phe6,Leu-NHEt13,des-Met14]-BN(6-14)] and Demotide 2 [(N4-CO-[D-Phe6,Leu-NHEt13,des-Met14]-BN(6-14)] had an IC50 of 2.6 nM ± 0.2 (n = 6) and 9.2 nM ± 2.7 (n = 6) respectively. Also 185/187 Re-PADA-AVA-bombesin(7-14) had an excellent IC50 of 4.9 nM ± 0.3 (n = 2), comparable to natural bombesin (4.5 nM ± 0.2 (n = 21)).
In NT receptor-expressing colon cancers and pancreatic cancers we found excellent affinities for the following stabilized NT radiopharmaceuticals: Demotide 4 [N4-Gly-Arg-y-Arg-Pro-Tyr-Tle-Leu] had an IC50 of 2.9 nM ± 0.4 (n = 4); the stabilized fluorobenzoyl (FB) neurotensin analogs [FB-Arg8y(CH2NH)Arg9]-NT(8-13) and [FB-Arg8y(CH2NH)Arg9-Tle12]-NT(8-13) had IC50's of respectively 0.91 nM ± 0.2 (n = 6) and 4.1 nM ± 0.6 (n = 6). Finally, four different Rhenium-labeled neurotensin analogs had binding affinities of 3.1 nM ± 0.1 (n = 4) [(NaHis)Ac-Lys-(yCH2NH)-Arg-Pro-Tyr-Tle-Leu], 0.77 nM ± 0.2 (n = 4) [(NaHis)Ac-Arg-(N-CH3)-Arg-Pro-Tyr-Tle-Leu], 2.1 nM ± 0.4 (n = 4) [(NaHis)Ac-bArg-Lys-Pro-Tyr-Tle-Leu] and 1.2 nM ± 0.2 (n = 4) [(NaHis)Ac-(N-CH3)-Arg-Lys-Pro-Tyr-Tle-Leu].
These results show that various stabilized peptide radiopharmaceuticals that can be labeled with different isotopes can successfully be developed; with their high binding affinity to human GRP and NT receptors, they are good candidates for in vivo targeting of GRP and NT receptor-positive human tumors.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
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Swiss Project-Number: 96.0447-3