[²¹³Bi]Bi³⁺/[¹¹¹In]In³⁺-neunpa-cycMSH: Theranostic Radiopharmaceutical Targeting Melanoma─Structural, Radiochemical, and Biological Evaluation

Abstract

With the emergence of [ 225 Ac]Ac 3+ as a therapeutic radionuclide for targeted α therapy (TAT), access to clinical quantities of the potent, short-lived α-emitter [ 213 Bi]Bi 3+ (t 1/2 = 45.6 min) will increase over the next decade. With this in mind, the nonadentate chelator, H 4 neunpa-NH 2 , has been investigated as a ligand for chelation of [ 213 Bi]Bi 3+ in combination with [ 111 In]In 3+ as a suitable radionuclidic pair for TAT and single photon emission computed tomography (SPECT) diagnostics. Nuclear magnetic resonance (NMR) spectroscopy was utilized to assess the coordination characteristics of H 4 neunpa-NH 2 on complexation of [ nat Bi]Bi 3+ , while the solid-state structure of [ nat Bi][Bi(neunpa-NH 3 )] was characterized via X-ray diffraction (XRD) studies, and density functional theory (DFT) calculations were performed to elucidate the conformational geometries of the metal complex in solution. H 4 neunpa-NH 2 exhibited fast complexation kinetics with [ 213 Bi]Bi 3+ at RT achieving quantitative radiolabeling within 5 min at 10 −8 M ligand concentration, which was accompanied by the formation of a kinetically inert complex. Two bioconjugates incorporating the melanocortin 1 receptor (MC1R) targeting peptide Nle-CycMSH hex were synthesized featuring two different covalent linkers for in vivo evaluation with [ 213 Bi]Bi 3+ and [ 111 In]In 3+ . High molar activities of 7.47 and 21.0 GBq/μmol were achieved for each of the bioconjugates with [ 213 Bi]Bi 3+ . SPECT/CT scans of the [ 111 In]In 3+ -labeled tracer showed accumulation in the tumor over time, which was accompanied by high liver uptake and clearance via the hepatic pathway due to the high lipophilicity of the covalent linker. In vivo biodistribution studies in C57Bl/6J mice bearing B16-F10 tumor xenografts showed good tumor uptake (5.91% ID/g) at 1 h post-administration with [ 213 Bi][Bi(neunpa-Ph-Pip-Nle-CycMSH hex )]. This study demonstrates H 4 neunpa-NH 2 to be an effective chelating ligand for [ 213 Bi]Bi 3+ and [ 111 In]In 3+ , with promising characteristics for further development toward theranostic applications.

H4picoopa─Robust Chelate for 225Ac/111In Theranostics

“…In the case of bioconjugate ( 17 ), the radiolabeling studies showed poorer RCCs with both [ 225 Ac]­Ac 3+ and [ 111 In]­In 3+ compared to the “free” chelator ( 14 ), while bioconjugate ( 19 ) showed more competitive complexation at low concentrations. This observation is consistent with the results previously reported for H 4 neunpa, which showed superior radiolabeling with [ 213 Bi]­Bi 3+ and [ 111 In]­In 3+ for bioconjugates featuring the elongated Aoc spacer between the chelator and CycMSH hex targeting vector.…”

“…While the in vivo studies of [ 111 In]­[In­(picoopa-Bn-Aoc-Pip-Nle-CycMSH hex )] − were somewhat disappointing from an imaging perspective, these results are directly comparable to the previously reported radiotracer [ 111 In]­[In­(neunpa-Ph-Aoc-Pip-Nle-CycMSH hex )] − , which showed similarly high uptake in the liver (24.44 ± 4.99 %ID/g), spleen (28.67 ± 5.67 %ID/g), and kidneys (7.75 ± 0.37 %ID/g), and low tumor accumulation (1.64 ± 0.30 %ID/g) at 24 h post-administration . Free [ 111 In]­In 3+ is rapidly bound by human transferrin in vivo and transported to the liver and spleen; however, the [ 111 In]­[In­(neunpa)] − complex has been previously shown to remain stable in vivo up to 5 days post-administration .…”

Bispidine Chelators for Radiopharmaceutical Applications with Lanthanide, Actinide, and Main Group Metal Ions

“…H 4 neunpa shows the highest RCY for bismuth labeling, and quantitative complex formation was reported for very small amounts of this chelator (10 −8 M) at ambient temperature after incubation for 5−7 min. 17 However, both bispidines allow labeling at remarkably high molar activities, with values of 0.25 MBq/nmol for L 2 and 2.5 MBq/nmol for L 3 . Quantitative radiolabeling with [ 133 La]LaCl 3 was achieved with 10 μmol/L L 2 at a slightly increased temperature (40 °C) after incubation for 60 min (Figure 6).…”

“…16,17 Specifically with [ 225 Ac]Ac 3+ , complexation requires up to half an hour at 80 °C for quantitative labeling, and this is not suitable for use with heat-sensitive targeting moieties such as antibodies. 17 Faster complexation under mild conditions is achieved with the open-chain and macrocyclic patype ligands (pa = picolinic acid). 16−18 Ligands with the bispidine backbone (e.g., L 1 −L 3 ) are known to be favorable with respect to metal ion selectivity, high complex stability, efficient complexation kinetics, and inertness, 19 and this is due to their open-chain nature, a rigid cavity with a favorable size and shape, in particular for tetragonal symmetry and relatively large metal ions (see Figure 1), 20,21 and due to the possibility of decorating the scaffold with pendant donor groups with well-tuned electronic and geometric properties.…”

Radiometallation and photo-triggered release of ready-to-inject radiopharmaceuticals from the solid phase

“…12 This is inherently difficult to implement, especially for the radiolabeling with metal-ions and metalloids, which are usually separated under highly acidic conditions (2–12 M HCl) 13,14 from their parent nuclide using ion-exchange chromatography but subsequently require much milder, aqueous radiosynthesis conditions for stable chelate formation. 15–17 Specifically, bifunctional chelators, peptides and biomolecules utilized as disease-specific targeting vectors typically require a pH range of 4–8 to form stable complexes. 18–22…”