Novel dimeric DOTA-coupled peptidic Y1-receptor antagonists for targeting of neuropeptide Y receptor-expressing cancersReportar como inadecuado

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EJNMMI Research

, 1:21

First Online: 02 September 2011Received: 14 April 2011Accepted: 02 September 2011


BackgroundSeveral peptide hormone receptors were identified that are specifically over-expressed on the cell surface of certain human tumors. For example, high incidence and density of the Y1 subtype of neuropeptide Y NPY receptors are found in breast tumors. Recently, we demonstrated that the use of potent radiolabeled somatostatin or bombesin receptor antagonists considerably improved the sensitivity of in vivo imaging when compared to agonists. We report here on the first DOTA-coupled peptidic Y1 receptor affine dimer antagonists.

MethodsBased on a Y1 affine dimeric peptide scaffold previously reported to competitively antagonize NPY-mediated processes, we have developed new dimeric DOTA-coupled Y1 receptor affine antagonists for scintigraphy and radiotherapy. These dimeric peptides were tested for their specific binding to Y1 expressed in SK-N-MC cells and Y2 expressed in SH-SY5Y as well as for their ability to mediate cAMP production in SK-N-MC cells.

ResultsIntroduction of two DOTA moieties at the N-termini of the dimeric NPY analogs as well as the double Asn replacement by DprDOTA or LysDOTA 6 and 10 moiety dramatically reduced binding affinity. However, asymmetric introduction of the DOTA moiety in one segment of the peptidic heterodimer 8 and 11 resulted in suitable antagonists for receptor targeting with high binding affinity for Y1. All compounds were devoid of Y2 binding affinity.

ConclusionsThe design and the in vitro characterization of the first DOTA-coupled dimeric NPY receptor antagonist with high affinity and selectivity for Y1 over Y2 are described. This compound may be an excellent candidate for the imaging of Y1-positive tumors and their treatment.

Keywordsneuropeptide Y receptor tumor imaging oncology peptide receptor radionuclide therapy breast cancer antagonist AbbreviationsThe abbreviations for the common amino acids are in accordance with the recommendations of 38. Additional abbreviationsAcm: acetamidomethyl


BSAbovine serum albumin

cAMP3-,5-cyclic adenosine monophosphate


CZEcapillary zone electrophoresis


DICN, N-diisopropylcarbodiimide

DIPEAN, N-diisopropylethylamine



DOTA1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

Dpr2,3-diaminopropionic acid

FBSfetal bovine serum




MALDI-TOF-MSmatrix assisted laser desorption-ionization-time off light mass spectrometry


MEMminimum essential medium


NMRnuclear magnetic resonance


NPYneuropeptide Y


PPpancreatic polypeptide

PYYpeptide YY

RP-HPLCreversed-phase high-performance liquid chromatography


TEAPtriethylammonium phosphate

TFAtrifluoroacetic acid.

Electronic supplementary materialThe online version of this article doi:10.1186-2191-219X-1-21 contains supplementary material, which is available to authorized users.

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Autor: David Chatenet - Renzo Cescato - Beatrice Waser - Judit Erchegyi - Jean E Rivier - Jean Claude Reubi


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