Development and characterization of two novel ⁶⁸Ga‐labelled neuropeptide Y short analogues with potential application in breast cancer imaging

Abstract

In vivo receptor targeting with radiolabelled peptide‐based probes is an attractive approach for the development of novel radiotracers for molecular imaging. This work presents the development and characterization of two novel neuropeptide Y analogues labelled with a positron emitter 68Ga, for potential use in breast cancer imaging. Both analogues share the same amino acid sequence and were derivatized with NOTA through either a lysine linker (L1) or an acetylated lysine (L2). In both cases, a single product with radiochemical purity higher than 95% was obtained. The two complexes were hydrophilic, showed remarkable in vitro stability, good cellular uptake, binding affinity in the nanomolar range and high cellular internalization rate. Biodistribution studies revealed low blood uptake and elimination through the urinary tract. The addition of an acetyl group in the spacer increased the lipophilicity of C2 and modified the reactivity of the ε‐amino group of the lysine which resulted in lower protein binding and lower percentage of injected dose in bladder and urine. The tumour versus muscle ratio was (3.8 ± 0.4) for 68Ga‐L1 and (4.7 ± 0.4) for 68Ga‐L2. These results encourage performing further studies in order to complete the evaluation of both tracers as potential radiopharmaceutical for breast cancer imaging.

Neuropeptide Y Peptide Family and Cancer: Antitumor Therapeutic Strategies

“…The development of multifunctional NPY-conjugates for selective nuclear delivery of radio lanthanides (targeted radionuclide therapy) is a promising strategy to deliver therapeutically active cargos (e.g., radiometals) into tumor cells overexpressing peptide receptors (e.g., Y1R) [ 255 ]. Novel 68 Ga-labeled NPY, short analogs with potential applications in cancer imaging, have been developed [ 256 ]. Moreover, 99 mTc-labeled NPY short analogs showing Y1R affinity and potential applications in cancer imaging have been reported: in vitro studies demonstrated a specific cellular uptake and a high internalization rate, whereas the IC 50 was 73.2 nM [ 257 ].…”

PET Imaging of the Neuropeptide Y System: A Systematic Review

“…More recently, still focusing on in vivo receptor targeting with radiolabeled peptidebased probes, Cardoso et al described the development and characterization of two 68 Ga-labeled NPY analogues for their potential use in breast cancer diagnosis [134]. Both of the analogues shared the same amino acid sequence: Tyr-Arg-Leu-Arg-BPA-Nle-Pro-Asn-Ile (BPA: L-4-benzoylphenylalanine), one which favors preferential binding to NPY Y 1 receptors, and were derivatized with NOTA (Figure 10) through a lysine (35a) or an acetylated lysine (35b) linker.…”

“…Both of the analogues shared the same amino acid sequence: Tyr-Arg-Leu-Arg-BPA-Nle-Pro-Asn-Ile (BPA: L-4-benzoylphenylalanine), one which favors preferential binding to NPY Y 1 receptors, and were derivatized with NOTA (Figure 10) through a lysine (35a) or an acetylated lysine (35b) linker. More recently, still focusing on in vivo receptor targeting with radiolabeled peptidebased probes, Cardoso et al described the development and characterization of two 68 Galabeled NPY analogues for their potential use in breast cancer diagnosis [134]. Both of the analogues shared the same amino acid sequence: Tyr-Arg-Leu-Arg-BPA-Nle-Pro-Asn-Ile (BPA: L-4-benzoylphenylalanine), one which favors preferential binding to NPY Y1 receptors, and were derivatized with NOTA (Figure 10) through a lysine (35a) or an acetylated lysine (35b) linker.…”