Charron C L, McFarland M S, Dhanvantari S, Luyt L G
Department of Chemistry , University of Western Ontario , 1151 Richmond Street , London , Ontario N6A 5B7 , Canada . Email:
Lawson Health Research Institute , 268 Grosvenor Street , London , Ontario N6A 4V2 , Canada.
Medchemcomm. 2018 Sep 17;9(10):1761-1767. doi: 10.1039/c8md00210j. eCollection 2018 Oct 1.
The ghrelin receptor is a member of the growth hormone secretagogue receptor (GHS-R) family and is present at low concentrations in tissues such as the brain, kidney, cardiovascular system, and prostate. The ghrelin receptor plays an important role in cellular proliferation, apoptosis, invasion, and migration associated with the progression of many cancers, including prostate, breast, ovarian, testicular, and intestinal carcinomas. Ghrelin, the endogenous ligand, is a 28 amino acid peptide (IC = 3.1 nM) known to have poor stability. Herein, we report the synthesis and evaluation of [Dpr(octanoyl),Lys(Ga-DOTA)]ghrelin(1-19). This new ghrelin analogue has a binding affinity (IC = 5.9 nM) comparable to that of natural ghrelin. Preliminary evaluation shows higher uptake of [Dpr(octanoyl),Lys(Ga-DOTA)]ghrelin(1-19) in HT1080/GHSR-1a xenografts than the non-transfected HT1080 xenografts in NOD-SCID mice, although considerable uptake is observed in the kidneys. This is the first example of ghrelin receptor PET imaging in a xenograft model using a peptide derived directly from the endogenous ligand and serves as motivation for developing more effective ghrelin-based radiopeptides.
胃饥饿素受体是生长激素促分泌素受体（GHS-R）家族的成员，在脑、肾、心血管系统和前列腺等组织中以低浓度存在。胃饥饿素受体在与许多癌症进展相关的细胞增殖、凋亡、侵袭和迁移中起重要作用，这些癌症包括前列腺癌、乳腺癌、卵巢癌、睾丸癌和肠癌。内源性配体胃饥饿素是一种由28个氨基酸组成的肽（IC = 3.1 nM），已知其稳定性较差。在此，我们报告了[Dpr（辛酰基），Lys（Ga-DOTA）]胃饥饿素（1-19）的合成与评估。这种新的胃饥饿素类似物具有与天然胃饥饿素相当的结合亲和力（IC = 5.9 nM）。初步评估显示，在NOD-SCID小鼠中，[Dpr（辛酰基），Lys（Ga-DOTA）]胃饥饿素（1-19）在HT1080/GHSR-1a异种移植瘤中的摄取高于未转染的HT1080异种移植瘤，尽管在肾脏中也观察到相当多的摄取。这是在异种移植模型中使用直接源自内源性配体的肽进行胃饥饿素受体PET成像的首个实例，并为开发更有效的基于胃饥饿素的放射性肽提供了动力。
