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Objectives Bispidines (3,7-diazabicyclo[3.3.1]nonanes) are of great interest for the use in radiopharmaceutical applications. Combining the advantages of highly preorganised rigid macrocyclic ligands and the flexibility of open-chain ligands, they are able to form highly stable complexes at mild reaction conditions with a broad range of di- and trivalent metal ions.1,2 Here, we present a nonadentate bispidine ligand (Fig. 1) labelled with [177Lu]LuCl3, [225Ac]AcCl3 and [111In]InCl3 at mild conditions and report their stability and inertness in aqueous solution and human serum.3 The results in terms of radiolabelling conditions and serum stabilities are compared with the “gold standard” DOTA, which requires harsh radiolabelling conditions, and the octadentate bispidine ligand H2bispa.2,4 Methods The bispidine ligand was synthesised according to literature on a multigram scale, with an overall yield of 5% over 9 steps.2 Radiolabelling experiments of the nonadentate bispidine ligand with [177Lu]Lu3+ and [225Ac]Ac3+ were carried out at 40 °C using 150 mM NH4OAc buffer (pH 6). Radiolabelling with [111In]In3+ was performed in the same buffer at room temperature. For comparison, the DOTA and the octadentate bispidine ligand H2bispa2 were labelled with the trivalent radiometals as well. The radiochemical yields and purities were monitored via radio-TLC and radio-HPLC for different ligand concentrations after 5 min, 30 min and 60 min. Radiostabilities in human serum were studied by radio-TLC and radio-SEC after 1 h, 1 d, 3 d and 7 d. Results Radiolabelling experiments gave quantitative yields for the formation of both 177Lu- and 225Ac‑complexes at 40 °C after 5 minutes for ligand concentrations of 10-6 mol/L. With [111In]In3+ a quantitative conversion was obtained even at room temperature after 60 minutes with a ligand concentration of 5·10-6 mol/L. For [177Lu]Lu3+, a molar activity of >100 MBq/nmol, for [225Ac]Ac3+ 0.2 MBq/nmol and for [111In]In3+ >20 MBq/nmol was found at the end of synthesis. Furthermore, the radiolabelled bispidine complexes showed high stability in human serum after 7 d ([225Ac]Ac‑bispidine: 80±2%; n=3, [177Lu]Lu-bispidine: 94%; n=2,), whereas only moderate stability was achieved for [111In]In-bispidine (74%; n=2 ) after 3 d. Conclusions The presented 177Lu- and 225Ac-labelled bispidine complexes showed favourable labelling kinetics and radiostabilities in human serum. The 111In-labelled bispidine gave moderate molar activities and stabilities in human serum. In comparison to DOTA, milder conditions for bispidine ligands allow the radiolabelling of heat-sensitive biomolecules. References [1] Comba, P.; Kerscher, M.; Rück, K.; Starke, M. Bispidines for Radiopharmaceuticals. Dalton Trans. 2018, 47, 9202–9220. [2] Abad‐Galán, L.; Cieslik, P.; Comba, P.; Gast, M.; Maury, O.; Neupert, L.; Roux, A.; Wadepohl, H. Excited State Properties of Lanthanide(III) Complexes with a Nonadentate Bispidine Ligand. Chem. – Eur. J. 2021, 27, 10303–10312. [3] Cieslik, P.; Kubeil, M.; Stephan, H.; Comba, P. Bispidine derivatives and the use thereof. EP20216739, 2020. [4] Comba, P; Jermilova, U.; Orvig, C.; Patrick, B. O.; Ramogida, C.; Rueck, K.; Schneider, C.; Starke, M. Inorg. Chem. 2017, 23, 15945 – 15956.

Bispidines (3,7-diazabicyclo[3.3.1]nonane) and their derivatives act as bifunctional chelators (BFC), combining the advantages of multidentate macrocyclic and acyclic ligands (e.g., high kinetic inertness, rapid radiolabelling under mild conditions) [1]. This bicyclic chelator system shows a great diversity in terms of its denticity and type of functional groups, yielding a wide range of multidentate ligands that can bind a variety of different metal ions [1-3]. In addition, they allow a facile functionalisation of targeting molecules such as peptides, peptidomimetics, and bispecific antibodies which can also be used as target modules for adapter CAR T-cell cross-linkage [1, 4]. Herein, we present a nonadentate bispidine ligand labelled with [177Lu]Lu3+ and [225Ac]Ac3+ at mild conditions. The radiometal complexes have been obtained with high radiochemical yields (99%) and are stable in human serum [3]. This is unique so far, as many chelators are not able to bind both LuIII and AcIII under mild conditions (physiological pH, T100 MBq/nmol for [177Lu]Lu3+ and ~0.2 MBq/nmol for [225Ac]Ac3+). For targeting, the chelator was functionalised with a peptidic somatostatin analogue (Tyr3 -octreotate), which addresses the somatostatin subtype receptor 2 in neuroendocrine tumours. Both 177Lu(III)- and 225Ac(III)-labelled conjugates were investigated towards their binding affinity and internalization in a murine pheochromocytoma (MPC) and human pancreatic carcinoid (BON1) tumour cell line and were compared with [177Lu]Lu(III)- and [ 225Ac]Ac(III)-DOTA-TATE. The presented 177Lu(III)- and 225Ac(III)-labelled bispidine-conjugates show favourable labelling kinetics and high radiostabilities in human serum. The radioconjugates exhibited dissociation constants in the lower nanomolar range (95 %) in both cell lines. In comparison to the corresponding DOTA-radioconjugates, milder radiolabelling conditions might facilitate the labelling of heat-sensitive biomolecules. Thus, this bispidine chelator shows promising characteristics for future nuclear medicine applications. References: [1] P. Comba et al., Dalton Trans. 2018, 47, 9202. [2] L. Abad‐Galán et al., Chem. Eur. J. 2021, 27, 10303. [3] P. Cieslik et al., Bispidine derivatives and the use thereof. EP20216739, 2020. [4] G. Singh et al., Chem. Eur. J. 2020, 26, 1989.

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Introduction: Evidence-based clinical guidelines play an important role in health care and can be a valuable source for quality indicators (QI). However, the link between guidelines and QI is often neglected. International methodological standards for the development of guideline-based QI are lacking.[for full text, please go to the a.m. URL], 18. Deutscher Kongress für Versorgungsforschung (DKVF)