[Lys(DOTA)(4)]BVD15, a novel and potent neuropeptide Y analog designed for Y-1 receptor-targeted breast tumor imaging

Department of Nuclear Medicine and Radiobiology, Centre d'Imagerie Moléculaire de Sherbrooke, Université de Sherbrooke, Québec, Canada.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 02/2010; 20(3):950-3. DOI: 10.1016/j.bmcl.2009.12.068
Source: PubMed


We substituted a truncated neuropeptide Y (NPY) analog, [Pro(30), Tyr(32), Leu(34)]NPY(28-36)NH(2) also called BVD15, at various positions with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7-10-tetraacetic acid) and evaluated the effect of the coupling position with the binding affinity for NPY Y(1) receptors (NPY1R). Our data suggest that [Lys(DOTA)(4)]BVD15 (K(i)=63+/-25 nM vs. K(i)=39+/-34 nM for BVD15) is a potent NPY analog suitable for radiolabeling with metallo positron emitters for PET imaging of breast cancer.

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    • "The above-discussed results suggest a possible value of the Y1R as a surrogate marker of the ER status in breast cancer. Moreover, receptors of regulatory peptides such as NPY are in the focus of approaches to tumor targeting and molecular imaging of cancer [6]–[11], [13], [14], [18]. Therefore, we investigated the effect of estradiol and tamoxifen treatment on the Y1R level in MCF-7 tumors growing subcutaneously in nude mice (Fig. 10). "
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    ABSTRACT: The neuropeptide Y (NPY) Y(1) receptor (Y(1)R) has been suggested as a tumor marker for in vivo imaging and as a therapeutic target. In view of the assumed link between estrogen receptor (ER) and Y(1)R in mammary carcinoma and with respect to the development of new diagnostic tools, we investigated the Y(1)R protein expression in human MCF-7 cell variants differing in ER content and sensitivity against antiestrogens. ER and Y(1)R expression were quantified by radioligand binding using [(3)H]-17β-estradiol and the Y(1)R selective antagonist [(3)H]-UR-MK114, respectively. The latter was used for cellular binding studies and for autoradiography of MCF-7 xenografts. The fluorescent ligands Cy5-pNPY (universal Y(1)R, Y(2)R and Y(5)R agonist) and UR-MK22 (selective Y(1)R antagonist), as well as the selective antagonists BIBP3226 (Y(1)R), BIIE0246 (Y(2)R) and CGP71683 (Y(5)R) were used to identify the NPY receptor subtype(s) by confocal microscopy. Y(1)R functionality was determined by mobilization of intracellular Ca(2+). Sensitivity of MCF-7 cells against antiestrogen 4-hydroxytamoxifen correlated directly with the ER content. The exclusive expression of Y(1)Rs was confirmed by confocal microscopy. The Y(1)R protein was up-regulated (100%) by 17β-estradiol (EC(50) 20 pM) and the predominant role of ERα was demonstrated by using the ERα-selective agonist "propylpyrazole triol". 17β-Estradiol-induced over-expression of functional Y(1)R protein was reverted by the antiestrogen fulvestrant (IC(50) 5 nM) in vitro. Furthermore, tamoxifen treatment of nude mice resulted in an almost total loss of Y(1)Rs in MCF-7 xenografts. In conclusion, the value of the Y(1)R as a target for therapy and imaging in breast cancer patients may be compromised due to Y(1)R down-regulation induced by hormonal (antiestrogen) treatment.
    Full-text · Article · Dec 2012 · PLoS ONE
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