The radiolytic degradation of vector molecules is a major factor affecting the shelf life of therapeutic radiopharmaceuticals. The development of time-stable dosage forms of radiopharmaceuticals is the key to their successful implementation in clinical practice. Using [¹⁷⁷Lu]Lu-PSMA-617 molecule as an example, the time dependence of the change in radiochemical purity (RCP, %) under radiolysis conditions was studied. The dependence of [¹⁷⁷Lu]Lu-PSMA-617 radiolysis on parameters such as time, radionuclide activity, buffer agent concentration, precursor amount, and preparation volume was evaluated. It was shown that the absorbed dose was the dominant factor influencing the RCP. The RCP value is inversely proportional to the absorbed dose in the [¹⁷⁷Lu]Lu-PSMA-617 preparation and has an exponential dependence. The lutetium-177 dose factor ψ (Gy·mL·MBq⁻¹) and PSMA-617 concentration-dependent dose constant κ (Gy⁻¹) were evaluated for absorbed dose estimation via computer modeling, chemical dosimetry, and radiochemical purity monitoring under various conditions. The further refinement and application of the dependencies found can be useful for predicting the RCP value at the stage of optimizing the composition of the finished dosage form of therapeutic radiopharmaceuticals. The influence of the buffer agent (sodium acetate) concentration on [¹⁷⁷Lu]Lu-PSMA-617 radiolytic degradation was shown and should be considered both when developing a dosage form, and when comparing the results of independent studies. The effectiveness of the addition of various stabilizing agents, such as DMSA, cysteine, gentisic acid, vanillin, methionine, adenine, dobesilic acid, thymine, uracil, nicotinamide, meglumine, and mannitol, in suppressing the effects of radiolysis was evaluated.

Background: Radiochemical purity is a key criterion for the quality of radiopharmaceuticals used in clinical practice. The joint improvement of analytical methods capable of identifying related radiochemical impurities and determining the actual radiochemical purity, as well as the improvement of synthesis methods to minimize the formation of possible radiochemical impurities, is integral to the implementation of high-tech nuclear medicine procedures. PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for prostate cancer, and [¹⁷⁷Lu]Lu-PSMA-617 and [¹⁷⁷Lu]Lu-PSMA^I&T have achieved global recognition as viable radiopharmaceuticals. Recently, it was shown that specific radiochemical impurities can form during the synthesis of [¹⁷⁷Lu]Lu-PSMA-617 because of a spontaneous, thermally mediated condensation of the Glu-C(O)-Lys fragment, resulting in the formation of three different cyclic forms (with no affinity for PSMA). During this study, we identified another impurity, a product of detachment of the Glu-CO fragment from PSMA-617, caused by heating. The total content of all four thermally mediated degradation products may reach 9–11% during classical incubation for 30 min at 95 °C, reducing the radiochemical purity to an unacceptable level (albeit with high levels of radiochemical conversion). It is reasonable to assume that the formation of similar impurities is characteristic of all PSMA-specific vectors that contain Glu-C(O)-Lys pharmacophores. Because the formation of these impurities directly depends on the temperature and incubation time, to reduce their content in the reaction mixture at the end of the synthesis, it is necessary to select conditions to achieve a high level of radiochemical conversion for the minimum possible time and/or at the minimum sufficient temperature. Methods: In this study, using [¹⁷⁷Lu]Lu-PSMA-617 as an example, we evaluated the efficiency of alternative methods of synthesis with microwave heating and co-solvent (ethanol) addition to ensure radiochemical yield and radiochemical purity in the shortest possible time and at the minimum necessary and sufficient synthesis temperature. Results: Both approaches achieved a significant reduction in the impurities content, while achieving satisfactory synthesis yields in a short time. In addition to improving the synthesis parameters and radiochemical purity, the use of microwave heating and the addition of ethanol reduces the negative influence of other auxiliaries on labeling kinetics. Notably, the addition of ethanol under certain conditions allowed [¹⁷⁷Lu]Lu-PSMA-617 to be synthesized at room temperature for only 10 min. This makes it possible to achieve exceptionally high real radiochemical purity of the preparations, determined only by the quality of the original precursor. The approaches considered in this study can be successfully applied to improve the synthesis process and quality parameters of the finished product, both for known radiopharmaceuticals and for those under development.

Особенности и практические аспекты определения радиохимической чистоты рецепторспецифичных препаратов лютеция-177 на примере [ 177 Lu]Lu–PSMA-617

The binding of ⁶⁸Ga to two organic ligands containing aminodiphosphonic groups (1,7-diamino-4-oxaheptane-1,1,7,7-tetraphosphonic and 1,7-diamino-4-hydroxycarbonylheptane-1,1,7,7-tetraphosphonic acids) has been examined. The stability and osteotropic potential of the labeled compounds have been evaluated.

A comparative study of samarium-153 complexation with several phosphonate ligands (acyclic and cyclen-based) was carried out. Methods of quality control of the resulting complexes were proposed, and their biological behavior was determined. It is noted that the biological behavior of the radionuclide compound is the principal criterion for choosing it as an active pharmaceutical substance for the development of radiopharmaceuticals.

Two new aminodiphosphonic acids derived from salicylic acid and its phosphonic analogue were prepared through a simple and efficient synthesis. 2-[(2-Amino-2,2-diphosphono)ethyloxy]-benzoic acid 8 and 2-[(2-amino-2,2-diphosphono)ethyloxy]-5-ethyl-phenylphosphonic acid 9 were evaluated for their applicability as ⁶⁸Ga binding bone-seeking agents. Protonation constants of 8 and 9 and stability constants of the Ga³⁺ complexes with 8 and 9 in water were determined. The stability constant of Ga³⁺ complex with fully phosphorylated acid 9 (logK_GaL = 31.92 ± 0.32) significantly exceeds stability constant of Ga³⁺ complex with 8 (logK_GaL = 26.63 ± 0.24). Ligands 8 and 9 are as effective for Ga³⁺ cation binding as ethylenediamine-N,N’-diacetic-N,N’-bis(methy1enephosphonic) acid and ethylenediamine-N,N,N’,N’-tetrakis(methylenephosphonic) acid, respectively. The labelling process and stability of [⁶⁸Ga]Ga-8 and [⁶⁸Ga]Ga-9 were studied. Both 8 and 9 readily form ⁶⁸Ga-complexes stable to ten-fold dilution with saline. However, in fetal bovine serum, only [⁶⁸Ga]Ga-9 was stable enough to be subject to biological evaluation. It was injected into rats with bone pathology and aseptic inflammation of soft tissues. For [⁶⁸Ga]Ga-9 in animals with a bone pathology model in 60 and 120 min after injection, a slight accumulation in the pathology site, stable blood percentage level, and moderate accumulation in the liver were observed. For animals with an aseptic inflammation, the accumulation of [⁶⁸Ga]Ga-9 in the pathology site was higher than that in animals with bone pathology. Moreover, the accumulation of [⁶⁸Ga]Ga-9 in inflammation sites was more stable than that for [⁶⁸Ga]Ga-citrate. The percentage of [⁶⁸Ga]Ga-9 in the blood decreased from 3.1% ID/g (60 min) to 1.5% ID/g (120 min). Accumulation in the liver was comparable to that obtained for [⁶⁸Ga]Ga-citrate.