Bifunctionalc helators as parts of modular metalbased radiopharmaceuticals are responsible for stable complexation of the radiometali on and for covalentl inkageb etween the complex and the targetingv ector.T oa void loss of complex stability, the bioconjugation strategy should not interfere with the radiometal chelation by occupying coordinating groups.T he C9 positiono ft he very stable Cu II chelator 3,7-diazabicyclo[3.3.1]nonane (bispidine) is virtually predestined to introduce functional groups for facile bioconjugation as this functionalisationd oes not disturb the metal binding centre. We describe the preparation and characterisationo faset of novel bispidine derivatives equipped with suitable functional groupsf or diverse bioconjugation reactions,i ncluding common amine coupling strategies( bispidine-isothiocyanate) and the Cu-frees train-promoted alkyne-azide cycloaddition.Wedemonstrate their functionality and versatility in an exemplary way by conjugation to an antibody-based biomolecule andv alidate the obtained conjugatei nv itro and in vivo.[a] Dr.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.
Scheme1.Synthetic approaches to bispidine-acetic acid 2,bispidine-amine 3,b ispidine-alkyne 4,bispidine-isothiocyanate 5 and bispidine-DBCO 6 by using the bispidine-9-ol 1 as the starting compound: (a) THF,sodium hydride (NaH), iodoacetic acid, H 2 O, 50 8C, 2h,y ield = 8.6 %; (b) (i)Dry THF, sodium hydride (NaH), tert-butyl(3-bromopropyl)carbamate, sodiumh ydrogen carbonate( NaHCO 3 ), 50 8C, 20 h, yield = 35 %, (ii)TFA/DCM, 1:1( v/v), RT, 24 h, yield = 100 %; (c)Dry THF,sodiumh ydride (NaH),p ropargyl bromide, sodium hydrogenc arbonate (NaHCO 3 ), 50 8C, 3h,y ield = 16 %; (d) DCM, TEA, p-phenylene diisothiocyanate,R T, 16 h, yield = 60 %; (e) DCM, DBCO-NHS ester, TEA, RT,2h, yield = 56 %.