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A sterically encumbered [[N.sub.2][S.sub.6]] macropentacycle related to diazamacrobicycles and cryptands is prepared by the [1!] condensation reaction between functionalized macrocyclic and macrotricyclic precursors. Adoption of the in, out form by macropentacycle in the crystal and in solution at low-temperature has resulted from the steric crowding and strain introduced by the [15]ane-[N.sub.2][S.sub.2] macrocyclic bridging subunits.

Study reports in detail the proporties of the proton complex of macropentacycle, correlations between the structures in the solid state and in solution, slow kinetics of formation, induction of the sense of chirality by optically active 1,1'-binaphthyl-2,2'-diyl phosphate anion.

Abstract: Two tripods (1 and 2) featuring pyrimidinyl pendant arms have been synthesized from 5-(1H-pyrazol-3-yl)-pyrimidine (5) and 1,3,5-tribromomethylbenzene derivatives. Reaction with three equivalents of [Pd(bipy)](NO3)2 to form a macrotricycle closed by palladium coordination unexpectedly afforded the mononuclear species [Pd(1)(bipy)]2+ and [Pd(2)(bipy)]2+ . These complexes show fluxional behavior on the 1H NMR timescale, the [Pd(bipy)]2+ fragment hopping between the pyrimidinyl coordinating moieties. The ΔG c ‡’s estimated by the coalescence method are temperature independent, which means that ΔS c ‡ =0. This indicates that the “merry-go-round” process of [Pd(bipy)]2+ occurs intramolecularly, presumably by nucleophilic attack of the free pyrimidinyl arm to the bound Pd2+ center. This phenomenon permits to quantify the lability of the Pd–N coordination bond, the average ΔG c ‡ ≈ ΔH c ‡ value being 70kJmol–1. [Copyright &y& Elsevier]

A sterically encumbered [N2S6] macropentacycle (5) related to diazamacrobicycles and cryptands has been synthesized in 53% yield by the [1+1] condensation reaction between functionalized macrocyclic and macrotricyclic precursors. A macrononacycle (18) resulting from the corresponding [2+2] condensation was isolated in 7% yield from the reaction mixture. Both compounds showed broad features in their room-temperature 1H NMR spectra, but their maximal average symmetry (D3h, and D2h, respectively) was achieved at high temperature (380 K). At low temperature (200 K, CD2CI2 solution), the macropentacycle is "frozen" to a single asymmetric (C1) conformation on the 1H NMR time scale, which has also the molecular structure observed in the solid state by X-ray crystallography: pseudo-triple helical (≠C3) shape, io (in, out) form resulting from the endo/exo configuration at the nitrogen bridgehead atoms, and similar orientations of the tosyl substituents. The solution dynamics of the molecule can be described by coupled bridgehead nitrogen inversion, triple helix symmetrization, and reversal of triple helix handedness, with ΔGc‡ = 54.2 kJ mol-1 in CD2CI2 at 300K. Adoption of the io form by macropentacycle 5 in the crystal and in solution at low-temperature most probably results from the steric crowding and strain introduced by the [15]ane-N2S2 macrocyclic bridging subunits. [ABSTRACT FROM AUTHOR]

227 Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223 Ra as its first daughter. There is an ample supply of 227 Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f -block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227 Th 4+ for α-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid ( p -SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid ( p -SCN-Bn-HEHA), p -isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*- p- Phe-NCS), and macrocyclic 1,2-HOPO N -hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead 227 Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion 89 Zr-labeled PET agent. Results: 227 Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227 Th-HEHA-ofatumumab showed moderate in vitro stability. 227 Th-DFOcyclo*-ofatumumab presented excellent 227 Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. 227 Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). 227 Th-L804-ofatumumab coordinated 227 Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89 Zr-L804-ofatumumab, showed organ distribution matching that of 227 Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227 Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89 Zr/ 227 Th quantitative imaging and α-particle therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)