Kristina A Petrosova, Aleksandr S Lunev, Marat G Rakhimov, Aleksey E Machulkin, Natalia S Volkova, Fedor I Vasilevich, Anton A Larenkov
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引用次数: 0
Abstract
Introduction: Folate receptors (FR) have been considered a convenient target for different radiopharmaceuticals in recent years. Multifarious 68Ga-labeled folate conjugates have been proposed as promising agents for the PET imaging of FR-overexpressing malignant neoplasms. In addition, radiolabeled folate-based conjugates can be effective for imaging non-tumor pathological foci characterized by a pronounced cluster of activated macrophages. We previously reported that a conjugate of folic acid with the NODAGA-chelator, labeled with gallium-68 and containing a (His-Glu)2-tag ([68Ga]Ga-NODAGA-[Lys-(HE)2]-folic acid), is suitable for imaging tumor lesions characterized by an increased density of FR. Introduction of the (His-Glu)2-tag into the structure of the folate radioconjugate significantly reduced its accumulation in non-target tissues (e.g., kidneys), leaving the accumulation in tumors at least at the same level, and even increasing it. The present study assessed the suitability of the developed molecule (in comparison with the unmodified analog) for imaging foci of non-oncological etiology characterized by a pronounced macrophage response.
Methods: Systemic juvenile idiopathic arthritis (JIA), reproduced in Wistar rats, was used as the pathology model. Acute inflammatory processes of soft tissues of septic and aseptic etiologies were selected as differential models.
Results: The results obtained in this study showed a significantly elevated level of accumulation in the JIA focus compared to healthy rat paws and accumulation in the foci of differential models of the inflammatory process, which confirms the macrophage-mediated pathway of accumulation of the studied compounds. Simultaneously, the ratio of accumulation in pathology to accumulation in comparable healthy tissues in all studied pathologies was significantly high.
Conclusion: The data obtained allowed us to conclude the diagnostic potential of new radiolabeled folate-based conjugate with (His-Glu)2-tag for pharmacokinetic property optimization in the radionuclide diagnosis of rheumatoid and other diseases characterized by a pronounced macrophage immune response. The mathematical compartment model quantitatively confirmed that the additional (His-Glu)2 fragment introduced in the molecule acts in favor of potential radiopharmaceutical use to visualize inflammatory processes by positron emission tomography.
期刊介绍：
Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized.
These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field.
Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.
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