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Neurotensin (NT) and its high affinity receptor (NTR1) are involved in several neoplastic processes. Thus, NT-based radiopharmaceuticals are potential tracers for targeted diagnosis and therapy of NTR-positive tumours. A new analogue based on NT(8–13), NT-XIX, with the three enzymatic cleavage sites stabilised, was synthesised and tested. The synthesis was performed by Boc strategy. Labelling with 99mTc/188Re was performed using the tricarbonyl technique. Metabolic stability was tested in vitro and in vivo . NT-XIX was further characterised in vitro in HT-29 cells and in vivo in nude mice with HT-29 xenografts. NT-XIX showed much longer half-lives than non-stabilised analogues. Binding to NTR1 was highly specific, although the affinity was lower than that of natural NT. Bound activity rapidly internalised into HT-29 cells and 50% remained trapped after 24 h. In the time-course biodistribution, the highest uptake was found in the tumour at all p.i. times. In vivo uptake was specific, and accumulation of activity in the kidneys was low. Radioactivity clearance from healthy organs was faster than that from the tumour, resulting in improved tumour-to-tissue ratios and good SPECT/CT imaging. Treatment with 188Re-NT-XIX (30 MBq, in three or four fractions) decreased tumour growth by 50% after 3 weeks. The high in vivo stability and the favourable in vivo behaviour makes NT-XIX an excellent candidate for the imaging and therapy of NTR1-positive tumours. [ABSTRACT FROM AUTHOR]

Novel endomorphin-2 analogs containing the unusual amphiphilic amino acid ( R)- and ( S)-α-hydroxymethyltyrosine in position 1 and ( R)- and ( S)-α-hydroxymethylphenylalanine in the positions 3 and 4 were synthesized via the solid-phase method. The binding characteristics of the synthetic analogs may suggest that α-hydroxymethyl substitution of aminoacid residues influences the conformation of a peptide much more than simply increasing the local amphiphilic character of the peptide. [ABSTRACT FROM AUTHOR]

Novel endomorphin-2 analogs containing the unusual amphiphilic amino acid ( R)- and ( S)-α-hydroxymethyltyrosine in position 1 and ( R)- and ( S)-α-hydroxymethylphenylalanine in the positions 3 and 4 were synthesized via the solid-phase method. The binding characteristics of the synthetic analogs may suggest that α-hydroxymethyl substitution of amino acid residues influences the conformation of a peptide much more than simply increasing the local amphiphilic character of the peptide. [ABSTRACT FROM AUTHOR]

In a previous communication we reported the racemic synthesis of the cis peptide bond mimic α-benzyl-o-aminomethylphenylacetic acid and its incorporation in the cyclic somatostatin analogues c[α(R and S)Bn-o-AMPA-Phe-d-Trp-Lys-Thr ]. Since the epimeric peptides exhibit different binding affinities, we completed the structure-activity study with an asymmetric synthesis. A model for the solution conformation of c[α(R and S)Bn-o-AMPA-Phe-d-Trp-Lys-Thr ] is proposed on the basis of a 2D NMR study in CDOH and restrained molecular dynamics. [ABSTRACT FROM AUTHOR]

A new cis-peptide bond mimetic, α-benzyl- o-aminomethylphenylacetic acid, was synthesized and incorporated in a homodetic somatostatin analogue. Biological binding tests and 2D NMR conformational analysis indicate that the configuration of the bridge-unit asymmetric center and the orientation of the benzyl side chain play a key role in the biological activity of this type of somatostatin analogues. [ABSTRACT FROM AUTHOR]

A new and stereoselective method to synthesize hydroxyethylamine and hydroxymethylamide peptide bond isosteres is developed. The key step is the addition of 2-trimethylsilylthiazole to α-aminoaldehydes, followed by transformation to α-hydroxy-β-aminoaldehydes. The stereochemistry of the addition can be manipulated by the choice of the nitrogen substitution. The isosteres are easily synthesized via Solid Phase Peptide Synthesis, which rapidly gives the desired pseudopeptides. [ABSTRACT FROM AUTHOR]

The design process and the synthetic problems for the construction of conformationally constrained cyclic somatostatins are described. Highly potent analogs containing o-aminomethylphenylacetic acid or o-aminomethylphenylalanine are obtained. [ABSTRACT FROM AUTHOR]

Hydrophobic and aromatic interactions are most critical for membrane peptide receptor-ligand complex stability. We have hypothesized that proper location of hydrophilic counterparts to lipophilic and/or aromatic residues may stabilize complexation with the receptor pocket. In this work, we are presenting the biological consequences of introduction of a hydroxymethyl group into the α-position of phenylalanine or tyrosine residues of enkephalin or deltorphin analogues. The consequences of such a modification are strongly dependent on the position of the primary amino acid in the peptide chain. [ABSTRACT FROM AUTHOR]

During a study on the preparation of the conformationally restricted analogue of tryptophan into 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid 1 by a Pictet-Spengler condensation with formaldehyde, two side products were detected: N-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid 2 and a dimer 3 of two 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid units linked by a methylene group. Their structures were determined by HPLC-MS and 2D NMR spectroscopy. By changing the isolation procedure, the N-hydroxymethyl compound was removed. Treatment of the mixture with TFA in water converted the dimer into 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid 1. [ABSTRACT FROM AUTHOR]

In order to influence side-chain conformations and to increase the μ-agonist properties of the δ-selective opioid receptor δ-antagonist H-Tyr-Tic-Phe-Phe-NH, residues Tyr, Phe and Phe were replaced by their β-methyl-substituted stereoisomers. Synthesis of β-Me-Tyr was carried out in a stereoselective way. Incorporation of the modified amino acids was performed by SPPS. Receptor binding data and GPI and MVD bioassays were obtained for all stereoisomers, in general showing equal or slightly increased potencies. In the [( R,S)β-Me-Phe]analogue, the introduction of the β-methyl substituent restores signal transduction. [ABSTRACT FROM AUTHOR]