A systematic evaluation of the potential of PCTA-NCS ligand as a bifunctional chelating agent for design of 177Lu radiopharmaceuticals

Chemical Promiscuity of Non-Macrocyclic Multidentate Chelating Ligands for Radiometal Ions: H4neunpa-NH2 vs H4noneunpa

“…19 Our concurrent interest in this chelating ligand was focused on investigating the influence of exchanging donor groups (N vs O) within the backbone on metal ion selectivity and how the position of central functionalization impacts metal−chelate binding characteristics. The central nitrogen atom in the backbone of H 4 neunpa-NH 2 ( 6) is a stronger donor than the equivalent ethereal oxygen of H 4 noneunpa (12); however, the tertiary central amine imposes additional conformational restrictions and steric strain in the chelate framework. Thus, effective coordination will be largely dictated by the dominance of one of these characteristics over the other for metal ions requiring nonadentate chelation.…”

“…Developing bifunctional derivatives of existing chelating ligands can often be at the expense of strong metal binding. Modifications to chelate design typically involve functionalization of the backbone or pendant donor arms with a covalent appendage, conjugation through an existing donor group, or the advent of an entirely new framework, which can lead to drastic differences in metal ion selectivity or complex stability compared to the original chelate. − For instance, the well-established acyclic chelator p -NH 2 -Bn-CHX-A′′-dtpa exhibits major differences in stability, and thus efficacy, compared with the p -NH 2 -Bn-CHX-B′′-dtpa stereoisomer, owing to subtle differences in steric environments when complexed to relevant ions such as In 3+ , Lu 3+ , or Y 3+ . , An approach to overcome these complications has been to design an intrinsically bifunctional chelate incorporating a covalent motif within the framework without compromising the advantageous characteristics of the parent chelating ligand (e.g., denticity, chelate-ring size, symmetry). , This strategy offers a means for higher-throughput development and assessment of in vivo behavior, which can often be dramatically different from in vitro studies (i.e., serum stability assays, thermodynamic stability); however, careful consideration of the seemingly subtle impacts of chelate design is critical for establishing an effective, viable chelator based on this approach …”

Pyclen Tri-n-butylphosphonate Ester as Potential Chelator for Targeted Radiotherapy: From Yttrium(III) Complexation to 90Y Radiolabeling

“…For instance, PCTA derivatives have drawn the attention of researchers working in the field of PET imaging, in particular due to their ability to form stable complexes with 68 Ga . These works provide several alternatives to obtain bifunctional chelating agents (BCAs) derived from this pyclen-based ligand, which are necessary to allow vectorization of the radiopharmaceutical by bioconjugation with a specific targeting biomolecule.…”

The Chemical Scaffold of Theranostic Radiopharmaceuticals: Radionuclide, Bifunctional Chelator, and Pharmacokinetics Modifying Linker

“…Radionuclide 177 Lu is widely used in radiopharmaceuticals for cancer therapy. Several types of BFCA are used to form complexes with 177 Lu, such as DOTA and DTPA [ 144 , 184 , 185 ]. Although DOTA and derivatives have high efficiency for use as a 177 Lu chelator, the complex formation process takes a long time at room temperature.…”

“…In addition, the 177 Lu-PCTA-NCS complex did not show any significant uptake in some vital organs such as the liver. PCTA-NCS can be used for radiolabeling with temperature-sensitive biomolecules within a few minutes at room temperature [ 185 ].…”