Abstract
Neuropeptide Y Y1 receptors (Y1R) have been found to be overexpressed in a number of different tumours, such as breast, ovarian or renal cell cancer. In mammary carcinoma the high Y1R density together with its high incidence of 85% in primary human breast cancers and 100% in breast cancer derived lymph node metastases attracted special attention. Therefore, the aim of this study was the development of radioligands for Y1R imaging by positron emission tomography (PET) with a special emphasis on imaging agents with reduced lipophilicity to provide a PET ligand with improved biodistribution in comparison with previously published tracers targeting the Y1R. Three new radioligands based on BIBP3226, bearing an 18F-fluoroethoxy linker (12), an 18F-PEG-linker (13) or an 18F-fluoroglycosyl moiety (11) were radiosynthesised in high radioactivity yields. The new radioligands displayed Y1R affinities of 2.8 nM (12), 29 nM (13) and 208 nM (11) and were characterised in vitro regarding binding to human breast cancer MCF-7-Y1 cells and slices of tumour xenografts. In vivo, small animal PET studies were conducted in nude mice bearing MCF-7-Y1 tumours. The binding to tumours, solid tumour slices and tumour cells correlated well with the Y1R affinities. Although 12 and 13 showed displaceable and specific binding to Y1R in vitro and in vivo, the radioligands still need to be optimised to achieve higher tumour-to-background ratios for Y1R imaging by PET. Yet the present study is another step towards an optimized PET radioligand for imaging of Y1R in vivo.
Highlights
Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are 36 amino acid peptides forming a family of biologically active peptides, the so-called neuropeptide Y or pancreatic polypeptide family[1]
We have reported the first 18F-labelled analogue of NPY, [Pra4([18F]FGlc),Phe7,Pro34]NPY, which was synthesised by 18F-fluoroglycosylation using the corresponding alkyne-functionalised peptide[12]
The alkynylated labelling precursor 7 was prepared from amine 419 by guanidinylation of 4 with the isothiourea derivative 5 in the presence of mercury(II) chloride yielding intermediate 6, which was treated with trifluoroacetic acid (TFA) to obtain alkyne 7 (Fig. 1)
Summary
Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are 36 amino acid peptides forming a family of biologically active peptides, the so-called neuropeptide Y or pancreatic polypeptide family[1]. The high incidence of Y1Rs of 85% in malignant primary human breast tumours and 100% in breast cancer derived lymph node metastases attracted special attention, and the high receptor density. [Phe7,Pro34]pNPY showed the highest selectivity for Y1R over Y2R and Y5R (>1:3000-fold)[10] This compound was further developed towards a 99mTc-labelled radioligand, [99mTc]Tc(CO)3-NαHis-Ac-[Phe7,Pro34]-NPY, which was used in first human imaging studies[11]. Besides the peptidic NPY analogues, a number of non-peptide Y1R ligands have been reported, such as BIBP322613, BIBO330414, LY35789715 and Y1-97316. The latter was radiolabelled with fluorine-18, a positron emitting radionuclide with beneficial decay characteristics, i.e. a half-life of 110 min, a clean decay profile
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