A new class of radiopeptides for PET imaging of neuromedin-B receptor: 68Ga-ranatensin analogs??

MedChemComm Pub Date: 2016-04-28 DOI: 10.1039/C6MD00131A

Abstract

The neuromedin B receptor (NMB-R) is a promising target in several human processes, for instance thymic carcinoma, intestinal carcinoids, pruritus, etc. NMB-R Positron Emission Tomography (PET) molecular imaging may be of great value. We here report on the development of the first 68Ga-ranatensin analog. The ranatensin derivative (Aib-Gln-Trp-Ala-Val-Gly-His-Phe-Met-CONH2, RV_15) was synthesized and conjugated to the DOTA macrocycle with good yield. This chelator is particularly suitable for 68Ga (T1/2 = 67.71 min, β+ branching = 89.14%) radiolabeling. Radiochemical purity, hydrophilicity, stability, pharmacological properties, inhibitory concentrations (IC50) and biodistribution in normal strain-A mice were investigated. Radiochemical purity of the 68Ga-ranatensin analog was always >97%. The non-radioactive analog, natGa-DOTA–RV_15, was found to be hydrophilic and behaves like an agonist to NMB-R and GRP-R (gastrin-releasing-peptide receptor which is another subtype of bombesin receptor) (EC50 values of 5.6 ± 0.1 × 10?9 M and 2.1 ± 0.1 × 10?9 M, respectively). Moreover, it showed nanomolar binding inhibitory concentrations for human NMB-R (IC50 = 3.0 ± 1.1 × 10?8 M) and somewhat less for human GRP-R (IC50 = 3.2 ± 1.2 × 10?7 M) in a competitive binding assay. 68Ga-DOTA–RV_15 is stable in plasma up to 45 minutes. Finally, this 68Ga-ranatensin agonist demonstrated rapid blood and urinary clearances and uptake in the pancreas and kidneys in normal mice. In conclusion, we have developed a novel class of radiopeptide analogue which potentially could be used for NMB-R molecular imaging.

Graphical abstract: A new class of radiopeptides for PET imaging of neuromedin-B receptor: 68Ga-ranatensin analogs
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