Very stable CuII complexes of bispidines and their radiopharmaceutical behavior

Optimization of Pentadentate Bispidines as Bifunctional Chelators for64Cu Positron Emission Tomography (PET)

“…The most promising and synthetically available tetradentate ligand is the bis(p-MeO) substituted bispidine B2. 43 Importantly, the bispidine-based BFCs also bear various possibilities for their coupling to biomolecules (color coded in Chart 1), i.e., (a) the ester groups at C 1 and C 5 (ester hydrolysis or reduction to the corresponding primary alcohols), 44 (b) the carbonyl function at C 9 (reduction to a secondary alcohol; 45 this modification is also important to avoid an induced retro-Mannich reaction in vivo, resulting in the decomposition of the ligand and its complex), and (c) various functionalities at R 1 and R 2 (see below).…”

Copper(ii) chemistry of the functionalized macrocycle cyclam tetrapropionic acid

“…Tetraazamacrocyclic ligands, especially cyclam derivatives (cyclam = 1,4,8,11-tetraazatetradecane), specifically but not exclusively with acetate-substituted tertiary amine donor groups are among the most widely used BFC's, 8 and this is due to the high stability of [Cu(cyclam)] 2+ . 9 Apart from substituted cyclam derivatives, cross-and side-bridged tetraazamacrocycles have been shown to lead to higher stabilities, kinetic inertness and better resistance to Cu II/I reduction, [10][11][12][13][14][15] and other ligands such as the sar-type hexaaza cages, [16][17][18][19] triazacyclononane derivatives, 20 and bispidine-type ligands 21,22 have also been studied extensively, with various advantages in terms of the formation kinetics, thermodynamic stabilities, ease of biovector substitution and in vivo properties.…”

N,N-Alkylation Clarifies the Role of N- and O-Protonated Intermediates in Cyclen-Based 64Cu Radiopharmaceuticals

“…Over the past decades, several other classes of 64 Cu­[Cu II ] chelators have been identified as suitable agents for PET. ,,, Macrocyclic polyaminocarboxylates derived from cross-bridged (CB) cyclam provide impressive thermodynamic and kinetic stability through the constrained binding cavity; ,, however, these systems can require harsh and extended radiolabeling conditions incompatible with biological conjugating agents , without further modification. − Frameworks based on 1,4,7-triazacyclononane (tacn; e.g., NOTA) can display excellent stability and chelate 64 Cu­[Cu II ] rapidly under mild conditions, ,,, while further modifications to molecular charge, lipophilicity, and conjugation can lead to improved performance. ,,− Pre-organized polycyclic N -donor chelates based on bispidine (bispa) − and sarcophagi (SarAr) scaffolds − can enable mild radiolabeling conditions and reasonable in vivo stability. Functionalization can be low yielding due to unselective alkylation and the presence of multiple regioisomers; however, several effective approaches have been identified and clinical trials are ongoing. ,− ,− …”

“…Early recognition and treatment of cancer is imperative for patient survival, 1−3 which makes the advancement of theranostic tools and the unification of detection (e.g., positron emission tomography, PET) and therapy a decisive step toward improving life expectancy. 4−6 As access to cyclotron sources has become more readily available, radioisotopes of copper, 7−14 such as 64 Cu (t 1/2 = 12.7 h and β + = 653 keV) and 67 Cu (t 1/2 = 61.9 h and β − = 141 keV), have received increasing attention as theranostic pairs. 13,15,16 Macrocyclic polyaminocarboxylates based on cyclen (i.e., H 4 DOTA and H 3 DO3A, Figure 1) have been examined extensively as bifunctional chelators 17−22 and comprise nearly half of all active 6 4 Cu clinical trials (Table S1).…”