triazacyclononane and Prostatic-Neoplasms

Improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual-nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, which are based on common and widely available metal radionuclides. Dual-chelator conjugates, featuring interlinked cyclen- and triazacyclononane-based polyphosphinates DOTPI and TRAP, allow for strictly regioselective complexation of therapeutic (e.g.,

Topics: Animals; Aza Compounds; Chelating Agents; Cyclams; Dipeptides; Heterocyclic Compounds; Heterografts; Humans; Male; Mice, SCID; Neoplasm Transplantation; Phosphatidylinositol Phosphates; Phosphinic Acids; Piperidines; Positron-Emission Tomography; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Structure-Activity Relationship

Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with (64)Cu. In vitro stability and cellular uptake of (64)Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA-Tf conjugates tested, N-NE3TA-Tf was identified as the best conjugate for radiolabeling with (64)Cu. N-NE3TA-Tf rapidly bound to (64)Cu (>98% radiolabeling efficiency, 1min, RT), and (64)Cu-N-NE3TA-Tf remained stable in human serum for 2days and demonstrated high uptake in PC-3 cancer cells. (64)Cu-N-NE3TA-Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24h period. This bifunctional chelate presents highly efficient chelation chemistry with (64)Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with (64)Cu for potential use in PET imaging applications.

Topics: Animals; Aza Compounds; Cell Line, Tumor; Chelating Agents; Copper Radioisotopes; Drug Stability; Female; Half-Life; Male; Mice, SCID; Neoplasm Transplantation; Piperidines; Positron-Emission Tomography; Prostatic Neoplasms; Radiopharmaceuticals; Tissue Distribution; Transferrin