Kaloudi Aikaterini, Lymperis Emmanouil, Kanellopoulos Panagiotis, Waser Beatrice, de Jong Marion, Krenning Eric P, Reubi Jean Claude, Nock Berthold A, Maina Theodosia
Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", 15310 Athens, Greece.
Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland.
Pharmaceuticals (Basel). 2019 Mar 20;12(1):42. doi: 10.3390/ph12010042.
The overexpression of gastrin-releasing peptide receptors (GRPRs) in frequently occurring human tumors has provided the opportunity to use bombesin (BBN) analogs as radionuclide carriers to cancer sites for diagnostic and therapeutic purposes. We have been alternatively exploring human GRP motifs of higher GRPR selectivity compared to frog BBN sequences aiming to improve pharmacokinetic profiles. In the present study, we compared two differently truncated human endogenous GRP motifs: GRP(14⁻27) and GRP(18⁻27). An acyclic tetraamine was coupled at the N-terminus to allow for stable binding of the SPECT radionuclide Tc. Their biological profiles were compared in PC-3 cells and in mice without or with coinjection of phosphoramidon (PA) to induce transient neprilysin (NEP) inhibition in vivo. The two Tc-N₄-GRP(14/18⁻27) radioligands displayed similar biological behavior in mice. Coinjection of PA exerted a profound effect on in vivo stability and translated into notably improved radiolabel localization in PC-3 experimental tumors. Hence, this study has shown that promising Tc-radiotracers for SPECT imaging may indeed derive from human GRP sequences. Radiotracer bioavailability was found to be of major significance. It could be improved during in situ NEP inhibition resulting in drastically enhanced uptake in GRPR-expressing lesions.
胃泌素释放肽受体（GRPRs）在常见人类肿瘤中的过表达为利用蛙皮素（BBN）类似物作为放射性核素载体至癌症部位用于诊断和治疗目的提供了契机。我们一直在探索与蛙BBN序列相比具有更高GRPR选择性的人GRP基序，旨在改善药代动力学特征。在本研究中，我们比较了两种不同截短的人内源性GRP基序：GRP(14⁻27)和GRP(18⁻27)。在N端偶联一个无环四胺以允许单光子发射计算机断层扫描（SPECT）放射性核素锝（Tc）的稳定结合。在PC-3细胞以及在未注射或共注射磷酰胺素（PA）以在体内诱导短暂的中性内肽酶（NEP）抑制的小鼠中比较它们的生物学特性。两种Tc-N₄-GRP(14/18⁻27)放射性配体在小鼠中表现出相似的生物学行为。共注射PA对体内稳定性产生了深远影响，并转化为PC-3实验肿瘤中显著改善的放射性标记定位。因此，本研究表明，用于SPECT成像的有前景的Tc放射性示踪剂确实可能源自人GRP序列。发现放射性示踪剂的生物利用度至关重要。在原位NEP抑制过程中其可得到改善，从而导致在表达GRPR的病变中摄取大幅增强。
