Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities

Abstract

DOTA-conjugated peptides, such as [DOTA(0),Tyr(3)]octreotide (DOTATOC) and [DOTA(0),Tyr(3)]octreotate (DOTA-tate), can be labelled with radionuclides such as (90)Y, (111)In and (177)Lu. These radiolabelled somatostatin analogues are used for peptide receptor radionuclide therapy (PRRT). Radioligands for PRRT require high specific activities. However, although these radionuclides are produced without addition of carrier, contaminants are introduced during production and as decay products. In this study, parameters influencing the kinetics of labelling of DOTA-peptides were investigated and conditions were optimised to obtain the highest achievable specific activity. The effects of contaminants were systematically investigated, concentration dependently, in a test model mimicking conditions for labelling with minimal molar excess of DOTA-peptides over radionuclide. Kinetics of labelling of DOTA-peptides were optimal at pH 4-4.5; pH <4 strongly slowed down the kinetics. Above pH 5, reaction kinetics varied owing to the formation of radionuclide hydroxides. Labelling with (90)Y and (177)Lu was completed after 20 min at 80 degrees C, while labelling with (111)In was completed after 30 min at 100 degrees C. The effects of contaminants were systematically categorised, e.g. Cd(2+) is the target and decay product of (111)In, and it was found to be a strong competitor with (111)In for incorporation in DOTA. In contrast, Zr(4+) and Hf(4+), decay products of (90)Y and (177)Lu, respectively, did not interfere with the incorporation of these radionuclides. The following conclusions are drawn: (a) DOTA-peptides can be radiolabelled at high specific activity; (b) reaction kinetics differ for each radionuclide; and (c) reactions can be hampered by contaminants, such as target material and decay products.

Production of 177Lu for Targeted Radionuclide Therapy: Available Options

“…During irradiation, 177 Lu absorbs neutron and leads to the formation of 177/ 178 Hf, which results in the accumulation of the 177 / 178 Hf carrier in the target system. While the presence of 177/178 Hf(IV) has no consequences in the efficiency of 177 Lu(III)-labeling reactions [53], accumulation of hafnium atoms decreases the specific activity.…”

“…Under this premise, it is pertinent to note that owing to the long half-life and low neutron absorption cross section, the activity levels of 177m Lu formed will be low but still be of possible concern. Whereas the 177m Lu waste issue must be locally resolved, estimates have clearly shown that the resulting radiation dose increase from the presence of 177m Lu is insignificant at clinically significant dose levels, at least for PRRT [53]. Under the optimized production conditions, the reported values for the 177m Lu/ 177 Lu ratio vary between 0.01 %-0.02 % at EOB [57].…”

“…While the radiation dose to patients from 177m Lu (0.01 %-0.02 %) is of little consequence [53], the problem of safe handling and disposal of the residual quantities of 177m Lu by the hospital user may emerge as a major roadblock, which can hardly be circumvented, in principal, through the storage of the radioactive wastes that is customary in hospitals. Despite the above-mentioned drawbacks, however, 177 Lu obtained from the (n,γ) route is preferred by many hospitals owing to the cost-effective availability of acceptable quality and quantities on demand.…”

“…Fortunately, its presence is not of much concern owing to the negligible ingrowth and due to the fact that Hf does not interfere with the labeling [53].…”

Pre-clinical evaluation of [111In]-benzyl-DOTA-ZHER2:342, a potential agent for imaging of HER2 expression in malignant tumors

“…We used benzyl-DTPA in a previous study because of the easy and quick labeling at room temperature. Some publications (27,28) suggest that the use of DOTA derivatives requires heating up to 100˚C for efficient indium labeling, and that labeling at lower temperatures is rather inefficient (29). On the other hand, the gallium-DTPA complex is not considered to be sufficiently stable in vivo (30), and the use of PET with 68 Ga-labeled Z HER2:342 for visualization of HER2 would require the use of a macrocyclic chelator.…”