Breast‐Cancer Diagnosis by Neuropeptide Y Analogues: From Synthesis to Clinical Application

Abstract

In memory of Rainer RudolphBreast cancer is still one of the most frequently occurring tumors in women. Severe and often therapy-limiting side effects are a major obstacle in chemotherapy. New delivery concepts that reduce systemic side effects are needed to optimize anticancer therapies, and selective targeting concepts are required for early and selective tumor diagnosis. Neuropeptide Y (NPY), a member of the pancreatic polypeptide family, is a C-terminal amidated peptide hormone consisting of 36 amino acid residues.[1, 2] NPY-mediated functions are transmitted by so-called Y receptors, named Y 1 , Y 2 , and Y 5 receptors, which bind NPY with nanomolar affinity. All Y receptors are members of the class A of heptahelix receptors, that signal through heterotrimeric G proteins. [3,4] Reubi et al. have recently described Y-receptor expression in human breast cancer. They have shown that over 90 % of all breast tumors and 100 % of the examined metastases express Y 1 receptors.[5] Interestingly, a shift of the receptor subtype from Y 2 receptors in healthy tissue to Y 1 receptors during neoplasm was found, which is potentially related to reduced differentiation. Based on NPY and the known structure-activity relationships for Y 1 -receptor binding, [6] we designed, synthesized, and characterized two analogues for tumor labeling that vary in the position of the chelator to conjugate 99m Tc. Peptides 1 a and 2 a were synthesized with a N a -histidinyl acetyl (N a His-ac) chelator [7] at the N terminus, whereas peptides 1 b and 2 b were modified at the N e side chain of Lys 4 . The tridentate ligand N a His-ac is able to form stable and biologically active complexes. [8,9] Modification of the resin-bound peptide was performed by an efficient strategy (Scheme 1). In the first step, bromoacetic acid was activated by diisopropylcarbodiimide to form the corresponding anhydride. His(Trt)-OtBu was then added and the NHÀ CH bond was formed by HBr elimination. Cleavage of the peptide yielded His-acetyl peptides either at the N terminus or at the N e side chain of Lys 4 . Rhenium was used as a cold surrogate for 99m Tc and introduced for in vitro studies

Quantitative impedimetric NPY-receptor activation monitoring and signal pathway profiling in living cells

“…Moreover, NPY receptors are also expressed in many carcinomas, such as gastrointestinal tumors and breast cancer (Reubi et al, 2001(Reubi et al, , 2004. Especially in human breast carcinomas, there is a receptor expression shift from the Y2-to the Y1-receptor subtype, which offers the opportunity for specific tumor diagnostic and targeting (Khan et al, 2010). Development of novel NPY-receptor subtype specific therapeutics as well as diagnostics needs reliable methods for NPY-receptor detection and receptor activation monitoring.…”

Red-fluorescent argininamide-type NPY Y1 receptor antagonists as pharmacological tools

“…The Y 1 R was selected as a representative model of a peptidergic GPCR, for instance, as this receptor subtype was recently associated with diagnosis and treatment of tumours. [11][12][13][14][15][16][17][18][19] For the synthesis of non-peptidic fluorescent ligands, the argininamidetype Y 1 R selective antagonists BIBP 3226 20 and BIBO 3304 21 ( Fig. 1) were considered appropriate parent molecules to construct high affinity fluorescent probes with reduced propensity to induce internalisation compared to (peptidic) agonists.…”

Towards improved receptor targeting: anterograde transport, internalization and postendocytic trafficking of neuropeptide Y receptors

“…Beside the Y 1 receptorselective agonist for breast cancer diagnosis (Khan et al , 2010 ), various Y receptor agonists and antagonists have been developed for therapeutic applications. Among those are several Y 5 receptor antagonists designed for antiobesity medication.…”

“…Thus, radioactive or cytotoxic ligands can be applied that accumulate within the tumor cells subsequent to receptor stimulation and internalization. This enables improved diagnosis and therapy of distinct types of cancer and has been successfully shown for several GPCR, including the bombesin (gastrin-releasing peptide) and the Y 1 receptor (Santos -Cuevas et al, 2008 ;Khan et al , 2010 ) (Figure 2). …”