Synthesis, Characterization and In Vivo Studies of Cu(II)-64-Labeled Cross-Bridged Tetraazamacrocycle-amide Complexes as Models of Peptide Conjugate Imaging Agents

Copper-64, a positron emitter suitable for positron emission tomography (PET), demonstrates improved in
vivo clearance when chelated by the cross-bridged tetraazamacrocycle CB-TE2A compared to TETA. Good
in vivo clearance was also observed for 64Cu-CB-TE2A conjugated to a peptide, which converts one
coordinating carboxylate pendant arm to an amide. To better understand the in vivo stability of peptide-
conjugated CB-TE2A, cross-bridged monoamides were synthesized. Crystal structures of natCu(II)-CB-TEAMA and natCu(II)-CB-PhTEAMA revealed hexadentate, distorted octahedral coordination geometry. In
vivo biodistribution showed clearance of all 64Cu-radiolabeled cross-bridged monoamides from liver and
bone marrow such that uptake at 24 h was <10% of uptake at 30 min. In contrast, >60% of 30 min uptake
from 64Cu-TETA was retained in these tissues at 24 h. Clearance of 64Cu-cross-bridged monoamides from
nontarget organs suggests good in vivo stability, thus supporting the use of CB-TE2A as a bifunctional
chelator without modifications to the macrocycle backbone.