Evaluation of copper-labeled bifunctional chelate-albumin conjugates for blood pool imaging

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Abstract

62Cu (T12 = 9.8 min) is a generator-produced positron-emitting radionuclide with a half-life amenable to blood-pool imaging with PET. Three bifunctional chelates [cyclic anhydride of diethylenetriaminepentaacetic acid (cDTPAA), 6-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane-N,N′,N′',N′''-tetraacetic acid (BAT), and p-carboxyethylphenylglyoxal-bis-(4N-methyl-thiosemicarbazone (CE-DTS)] were conjugated to HSA and labeled with 67Cu. The labeling efficiency of 67Cu-DTS-HSA was > 90%, whereas the labeling yields of 67Cu-DTPA-HSA and 67Cu-benzyl-TETA-HSA were less than 70%. Blood clearance and biodistribution of these three 67Cu-labeled conjugates were determined in rats. Of the three 67Cu-labeled bifunctional chelate-HSA conjugates, 67Cu-benzyl-TETA-HSA remained in the blood pool the longest, achieving stable blood levels at times longer than 24 h post-injection. The 67Cu radioactivity cleared the blood within 60 min post-injection of 67Cu-DTS-HSA, and within 10 min after administration of 67Cu-DTPA-HSA, indicating the dissociation of Cu2+ from these conjugates. Copper-labeled DTS-HSA achieved stable blood concentrations for at least 30 min post-injection and was therefore evaluated as a vascular imaging agent. DTS-HSA and benzyl-TETA-HSA were labeled with 62Cu and administered to a dog for blood-pool imaging using PET. Images were nearly identical to an image taken after administration of C15O. Because of the high labeling efficiency, DTS-HSA can be labeled with 62Cu without purification, making it more practical than 62Cu-benzyl-TETA-HSA as a blood-pool imaging agent. Generator-produced 62Cu-DTS-HSA should be a viable alternative blood pool agent to cyclotronproduced C15O for PET facilities without cyclotrons.

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    Citation Excerpt :

    For ligands of the polyamine system, the macrocyclic chelators are more topologically constrained than the acyclic ones because of the absence of “head” and “end” groups in a ring,38 which provides the copper macrocyclic complexes with extra kinetic stability and thermodynamic stability as well. This is the reason why macrocyclic chelators have historically been used as BFCs to bind 67Cu(II) to antibodies rather than acyclic chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetetraaminepentaacetic acid (DTPA).32,39–41 Currently, the application of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) as a BFC for copper radiopharmaceuticals has advanced to clinic trials.42,43

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