title: Structure-Activity Relationship Studies of Amino Acid Substitutions in Radiolabeled Neurotensin Conjugates.
abstract: Radiolabeled derivatives of the peptide neurotensin (NT) and its binding sequence NT(8-13) have been studied as potential imaging probes and therapeutics for NT-1-receptor-positive cancer. However, a direct comparison of reported NT analogues, even if radiolabeled with the same radionuclide, is difficult because different techniques and models have been used for preclinical evaluations. In an effort to identify a suitable derivative of NT(8-13) for radiotracer development, we herein report a side-by-side in vitro comparison of radiometallated NT derivatives bearing some of the most commonly reported amino acid substitutions in their sequence. Performed investigations include cell internalization experiments, determinations of receptor affinity, measurements of the distribution coefficient, and blood serum stability studies. Of the [(177)Lu]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-labeled examples studied, analogues of NT(8-13) containing a short hydrophilic tetraethylene glycol (PEG4 ) spacer between the peptide and the radiometal complex, and a minimum number of substitutions of amino acid residues, exhibited the most promising properties in vitro.
authors.affiliation: Division of Radiopharmaceutical Chemistry, University of Basel Hospital, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Alba
authors.initials: A
authors.lastname: Mascarin
authors.affiliation: Division of Radiopharmaceutical Chemistry, University of Basel Hospital, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Ibai E
authors.initials: IE
authors.lastname: Valverde
authors.affiliation: Division of Radiopharmaceutical Chemistry, University of Basel Hospital, Petersgraben 4, 4031, Basel, Switzerland. t.mindt@gmx.ch.|Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland. t.mindt@gmx.ch.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Mindt
mesh_terms: D019943:Amino Acid Substitution; D019073:HT29 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000097:blood / Q000737:chemistry*; D006801:Humans; D008187:Lutetium / Q000097:blood / Q000737:chemistry*; D015394:Molecular Structure; D009496:Neurotensin / Q000097:blood / Q000737:chemistry*; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000097:blood / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D009496:Neurotensin; D008187:Lutetium
keywords: lutetium-177; neurotensin; peptides; radiopharmaceuticals; structure-activity relationships