²²⁵Ac-H₄py4pa for Targeted Alpha Therapy

Abstract

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t 1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10–6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La­(py4pa)]− anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La­(py4pa)]− complex also demonstrated a superb thermodynamic stability (log K [La(py4pa)] – ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K [La(DOTA)] – ∼ 24.25, pLa = 19.2) or H2macropa (log K [La(macropa)] – = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

“…As described by Miederer et al, 60% of Ac-225 was excreted after injection of [ 227 Ac]Ac-DTPA. Thus, the complexation of the free nuclides could be increased by chelator optimization [ 53 , 54 , 55 , 56 ], opting for 225 Ac-H4py4pa, for example [ 57 ]. However, further research has to be performed regarding this subject.…”

Ac-EAZY! Towards GMP-Compliant Module Syntheses of 225Ac-Labeled Peptides for Clinical Application

“…However, DOTA is not the ideal chelator for 225 Ac because of the long labeling time, high temperature, and the need for high molar amounts of precursor (10-20 µg/MBq) and, as a consequence, better chelators are currently under development [27][28][29][30][31][32]. For example, the chelator macropa forms stable 2 25 Ac-complexes within 5 min at room temperature and at lower precursor concentrations.…”

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications

“…DOTP 8- has been chelated with 225 Ac, compared with other 3+ cations, including Am, Cm, and La, and verified to be encapsulated within the DOTP 8- binding pocket [ 44 ]. Recently developed 225 Ac chelators such as H 4 py4pa and H 4 py4pa-phenyl-NCS have demonstrated excellent in vivo stability and tumor specificity [ 53 ]. Another novel chelator, 225 Ac-crown, was shown to be stable over an extended period of time, while binding rapidly to 225 Ac at ambient temperature [ 45 ].…”