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Background  Several 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 Y 1  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 Y 1  receptor affine dimer antagonists.    Methods  Based on a Y 1  affine dimeric peptide scaffold previously reported to competitively antagonize NPY-mediated processes, we have developed new dimeric DOTA-coupled Y 1  receptor affine antagonists for scintigraphy and radiotherapy. These dimeric peptides were tested for their specific binding to Y 1  expressed in SK-N-MC cells and Y 2  expressed in SH-SY5Y as well as for their ability to mediate cAMP production in SK-N-MC cells.    Results  Introduction of two DOTA moieties at the N-termini of the dimeric NPY analogs as well as the double Asn 29  replacement by Dpr(DOTA) or Lys(DOTA) ( 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 Y 1 . All compounds were devoid of Y 2  binding affinity.    Conclusions  The design and the  in vitro  characterization of the first DOTA-coupled dimeric NPY receptor antagonist with high affinity and selectivity for Y 1  over Y 2  are described. This compound may be an excellent candidate for the imaging of Y 1 -positive tumors and their treatment.

Novel dimeric DOTA-coupled peptidic Y1-receptor antagonists for targeting of neuropeptide Y receptor-expressing cancers