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báo cáo hóa học: " Novel dimeric DOTA-coupled peptidic Y1-receptor antagonists for targeting of neuropeptide Y receptor-expressing cancers"

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành hóa học dành cho các bạn yêu hóa học tham khảo đề tài: Novel dimeric DOTA-coupled peptidic Y1-receptor antagonists for targeting of neuropeptide Y receptor-expressing cancers | Chatenet et al. EJNMMI Research 2011 1 21 http www.ejnmmires.eom content 1 1 21 9 EJNMMI Research a SpringerOpen Journal ORIGINAL RESEARCH Open Access Novel dimeric DOTA-coupled peptidic Y1-receptor antagonists for targeting of neuropeptide Y receptor-expressing cancers 1.2 3 3 11 1.3 David Chatenet Renzo Cescato Beatrice Waser Judit Erchegyi Jean E Rivier and Jean Claude Reubi Abstract 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 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. Methods Based 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. Results Introduction of two DOTA moieties at the N-termini of the dimeric NPY analogs as well as the double Asn29 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 Y1. All compounds were devoid of Y2 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 Y1 over Y2 are described. This .