PMID- 33379299 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230830 IS - 1424-8247 (Print) IS - 1424-8247 (Electronic) IS - 1424-8247 (Linking) VI - 14 IP - 1 DP - 2020 Dec 28 TI - Selection of the First (99m)Tc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation-Preclinical Assessment of Two Optimized Candidates. LID - 10.3390/ph14010019 [doi] LID - 19 AB - Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project "TECANT" two (99m)Tc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [(99m)Tc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [(99m)Tc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [(99m)Tc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 degrees C) and lower dissociation rate (<30%, at 2 h/37 degrees C). In vivo, [(99m)Tc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [(99m)Tc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [(99m)Tc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 microSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [(99m)Tc]Tc-TECANT-1 for clinical translation of the first (99m)Tc-based SST2 antagonist. FAU - Fani, Melpomeni AU - Fani M AD - Division of Radiopharmaceutical Chemistry, University Hospital Basel, Universitatsspital Basel, CH-4031 Basel, Switzerland. FAU - Weingaertner, Viktoria AU - Weingaertner V AD - Department of Nuclear Medicine, Medical University Innsbruck, 6020 Innsbruck, Austria. FAU - Kolenc Peitl, Petra AU - Kolenc Peitl P AUID- ORCID: 0000-0003-4746-6740 AD - Department of Nuclear Medicine, University Medical Centre Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia. FAU - Mansi, Rosalba AU - Mansi R AUID- ORCID: 0000-0003-0342-8865 AD - Division of Radiopharmaceutical Chemistry, University Hospital Basel, Universitatsspital Basel, CH-4031 Basel, Switzerland. FAU - Gaonkar, Raghuvir H AU - Gaonkar RH AD - Division of Radiopharmaceutical Chemistry, University Hospital Basel, Universitatsspital Basel, CH-4031 Basel, Switzerland. FAU - Garnuszek, Piotr AU - Garnuszek P AD - Radioisotope Centre POLATOM, National Centre for Nuclear Research, 05-400 Otwock, Poland. FAU - Mikolajczak, Renata AU - Mikolajczak R AD - Radioisotope Centre POLATOM, National Centre for Nuclear Research, 05-400 Otwock, Poland. FAU - Novak, Doroteja AU - Novak D AD - Department of Nuclear Medicine, University Medical Centre Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia. FAU - Simoncic, Urban AU - Simoncic U AD - Faculty of Mathematics and Physics, University of Ljubljana, 1000 Ljubljana, Slovenia. FAU - Hubalewska-Dydejczyk, Alicja AU - Hubalewska-Dydejczyk A AD - Department of Endocrinology, Jagiellonian University Medical College, 31-008 Cracow, Poland. FAU - Rangger, Christine AU - Rangger C AUID- ORCID: 0000-0003-1167-9779 AD - Department of Nuclear Medicine, Medical University Innsbruck, 6020 Innsbruck, Austria. FAU - Kaeopookum, Piriya AU - Kaeopookum P AUID- ORCID: 0000-0001-8334-7701 AD - Department of Nuclear Medicine, Medical University Innsbruck, 6020 Innsbruck, Austria. FAU - Decristoforo, Clemens AU - Decristoforo C AUID- ORCID: 0000-0003-0566-4036 AD - Department of Nuclear Medicine, Medical University Innsbruck, 6020 Innsbruck, Austria. LA - eng GR - I 4220/FWF_/Austrian Science Fund FWF/Austria PT - Journal Article DEP - 20201228 PL - Switzerland TA - Pharmaceuticals (Basel) JT - Pharmaceuticals (Basel, Switzerland) JID - 101238453 PMC - PMC7824897 OTO - NOTNLM OT - SPECT/CT OT - SST2 OT - Tc-99m OT - neuroendocrine tumours OT - somatostatin receptor antagonist COIS- The authors declare no conflict of interest. EDAT- 2021/01/01 06:00 MHDA- 2021/01/01 06:01 PMCR- 2020/12/28 CRDT- 2020/12/31 01:03 PHST- 2020/12/04 00:00 [received] PHST- 2020/12/22 00:00 [revised] PHST- 2020/12/23 00:00 [accepted] PHST- 2020/12/31 01:03 [entrez] PHST- 2021/01/01 06:00 [pubmed] PHST- 2021/01/01 06:01 [medline] PHST- 2020/12/28 00:00 [pmc-release] AID - ph14010019 [pii] AID - pharmaceuticals-14-00019 [pii] AID - 10.3390/ph14010019 [doi] PST - epublish SO - Pharmaceuticals (Basel). 2020 Dec 28;14(1):19. doi: 10.3390/ph14010019.