Approaches to improve metabolic stability of a statine-based GRP receptor antagonist

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• 作者：Ilinca Popp^a ; Luigi Del Pozzo^a ; ^b ; ^c ; Beatrice Waser^d ; Jean Claude Reubi^d ; Philipp T. Meyer^a ; ^b ; ^c ; Helmut R. Maecke^a ; Eleni Gourni^a ; ^b ; ^c ; ^{eleni.gourni@medisin.uio.no}
• 关键词：Gastrin-releasing peptide receptor antagonists ; Metabolic stability ; 68Ga ; PET-imaging
• 刊名：Nuclear Medicine and Biology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：45
• 期：Complete
• 页码：22-29
• 全文大小：681 K
• 卷排序：45

文摘

The bombesin receptor family, in particular the gastrin-releasing peptide receptor (GRPr), is an attractive target in the field of nuclear oncology due to the high density of these receptors on the cell surface of several human tumors. The successful clinical implementation of 64Cu-CB-TE2A-AR06, 68Ga-RM2 and 68Ga-NODAGA-MJ9, prompted us to continue the development of GRPr-antagonists. The aim of the present study was to assess if N-terminal modulations of the statine-based GRPr-antagonist influence the binding affinity, the pharmacokinetic performance and the in vivo metabolic stability.MethodsThe GRPr-antagonist (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) was functionalized with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via the spacer 4-amino-1-carboxymethyl-piperidine (Pip) and the amino acid N-Methyl-β-Ala, to obtain NMe-RM2 and labeled with 68Ga and 177Lu. The GRPr affinity of the corresponding metalloconjugates determined using [125I–Tyr4]-BN as radioligand. In vitro evaluation included internalization studies using PC3 cells. The 68Ga-conjugate was evaluated in PC3 xenografts by biodistribution and PET studies, while investigations on the metabolic stability and plasma protein binding were performed.ResultsThe half maximum inhibitory concentrations (IC50) of the metalloconjugates, using [125I–Tyr4]-BN, are in the low nanomolar range. PC3-cell culture binding studies of both metallated NMe-RM2 and RM2 show high GRPr-bound activity and low internalization. Metabolic studies showed that 68Ga-NMe-RM2 and 68Ga-RM2 are being cleaved in a similar fashion into three metabolites, with a good proportion of about 50% of the remaining blood activity at 15 min post injection (p.i.) being represented by the intact radiotracer. 68Ga-NMe-RM2 was shown to target specifically PC3 xenografts, with high and sustained tumor uptake of about 13% IA/g within a time frame of 3 h. The PET images clearly visualized the tumor.ConclusionsThe relatively high percentage of the remaining intact radiotracer in blood 15 min post injection sufficiently enables in vivo targeting of GRPr positive tumors, finding which has been also shown in clinical trials.