In vivo behavior of copper-64-labeled methanephosphonate tetraaza macrocyclic ligands

Abstract

Copper-64 ( T(1/2)=12.7 h; beta(+): 0.653 MeV, 17.4%; beta(-): 0.578 MeV, 39%) is produced in a biomedical cyclotron and has applications in both imaging and therapy. Macrocyclic chelators are widely used as bifunctional chelators to bind copper radionuclides to antibodies and peptides owing to their relatively high kinetic stability. In this paper, we evaluated three tetraaza macrocyclic ligands with two, three, and four pendant methanephosphonate functional groups. DO2P [1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphonic acid)], DO3P [1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid)], and DOTP [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanephosphonic acid)] were all radiolabeled with (64)Cu in high radiochemical yields. Copper-64-labeled DO2P and DOTP were highly stable in rat serum out to 24 h, while (64)Cu-DO3P remained 73% intact, with the remainder possibly forming a (64)Cu(.)2DO3P dimer by 24 h. The biodistribution experiments were performed in normal Sprague-Dawley rats. Of the three complexes, (64)Cu-DO2P demonstrated the most optimal clearance through the blood and liver. Copper-64-DO3P and (64)Cu-DOTP exhibited higher liver uptake and longer retention of liver activity, possibly because of the large negative charge of the complexes under physiological conditions. All three (64)Cu-labeled complexes showed high accumulation in bone, likely due to the binding of the methanephosphonate groups to hydroxyapatite. These results suggest that this series of methanephosphonate macrocyclic ligands may be useful as potential bone-imaging agents. The thermodynamic stability constants of the Cu(II) complexes with these three ligands were determined, and were found to be significantly higher than those of their acetate analogues. The Cu(II)-DO2P complex exhibited the highest stability constant among divalent transition metal ion DO2P complexes. Metabolism studies of (64)Cu-DO2P in rat liver suggest that the DO2P ligand may be used as a bifunctional chelator for copper radionuclides in radiodiagnostic or radiotherapeutic studies.

Highly stable acyclic bifunctional chelator for 64Cu PET imaging

“…20.6 (2) a: Solvent: water; [43,44] 12.80 (8) 8.47(2)/6.39(2) 7.43 2.08 10.92 (2) In agreement with data available in the literature for polyaminomethanephosphonate derivatives (Table 2 and Chart 2) [40][41][42][43][44], the two higher protonation constants (log K L 1 H = 11.21(2) and log K L 1 H 2 = 10.29(2)) were attributed to the two tertiary amines. Interestingly, it has been shown for a series of compounds containing two geminal amino-N,N-bis(methanephosphonate) or amino-N-(methanephosphonate) units that the acido-basic properties of the tertiary amines can be drastically influenced by the length of the spacer connecting the two symmetrical sites (Table 2).…”

Molecular imaging with copper-64

“…The biodistribution of 64/67 Cu 2+ complexes of the polyaminophosphonate macrocyles and the bridged-cyclam ligands have also been reported [86,88]. Selected data from these studies are compared with those of polyaminotetraazamarocyclic complexes in Fig.…”

“…The breakdown of the complex or the association of the free radiometal ion with the serum is monitored for a time-frame comparable to the life-time of the target agent in the body. Table 6 summarises selected data from serum stability studies of various 64/67 Cu complexes [86,88,[101][102][103]. Unfortunately, a strict comparison can be difficult at times since not all radiometal ion complexes are at equimolar ratios of metal to ligand prior to incubation.…”

Dissociation kinetics study of Ce(III) complexes with H8dotp (H8dotp = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis (methylphosphonic acid))

“…The H 8 dotp was prepared according to a previously described procedure [10,11]. The complex was prepared by mixing metal ion solutions and the ligand in the solid state in the molar ratio 1:1.1 (10% ligand excess was used to ensure complete complex formation).…”