Mn(II)-alapú diagnosztikai szerek: az alapkutatástól a célzott diagnosztikai eljárásokig = Mn(II)-based diagnostic agents: From the basic research to targeted diagnostics

Váradi, Balázs and Sajtos, Gergő Zoltán and Brezovcsik, Károly and Szűcs, Zoltán and Szedlacsek, Stefan and Nagy, Gábor and Tircsó, Gyula (2024) Mn(II)-alapú diagnosztikai szerek: az alapkutatástól a célzott diagnosztikai eljárásokig = Mn(II)-based diagnostic agents: From the basic research to targeted diagnostics. SCIENTIA ET SECURITAS, 5 (2). pp. 253-266. ISSN 2732-2688

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Abstract

A célzott molekuláris képalkotás egy új, ígéretes módszer a nukleáris medicinában a diagnosztika és a terápia területén. A mangánizotópok sokszínűsége elérhető közelségbe hozta a bimodális képalkotásokat, mivel az 52 Mn pozitront emittáló izotóp a funkcionális PET, míg a paramágneses 55 Mn-izotóp kelátjai az MR kontrasztanyag-kutatások és a PET-diagnosztikumok kapcsolását tették lehetővé. Jelen közleményben kitérünk a Mn(II)-ion komplexálására leginkább alkalmas kelátorok, illetve az ezekből származtatható kétfunkciós és intelligens Mn(II)-komplexek, valamint a lehetséges biológiai vektormolekulák bemutatására. Ezekre az előzményekre alapozva példákat mutatunk be az in vivo kísérletek során jól teljesítő vektormolekulák és az általunk kifejlesztett kelátorok 52 Mn-izotóppal jelölt konjugátumainak alkalmazására. | Early diagnosis of oncological diseases is crucial for cancer treatment and survival. Imaging of cancerous tissues rely on the availability of targeting biovector molecules capable of carrying diagnostic medical radionuclides, contrast agents (CAs) or optical probes to the diseased tissue for imaging. The production of tissue-specific contrast agents or contrast agents targeted with appropriate vector molecules was fueled by their ability to accumulate in certain tissues or organs, which allows us to reduce the required dose or to visualize specific processes at the cellular/tissue level. Recent developments in antibody engineering and PET (positron emission tomography) radiochemistry have led to new ImmunoPET imaging approaches. In contrast to the antibodies, antibody fragments such as minibodies, diabodies, single-chain variable region fragments (scFvs), nanobodies and affibodies are smaller in size, yet retain the specificity and affinity of antibodies in addition to more desirable pharmacokinetic profiles. For such imaging studies isotopes with long half-lives are required (64Cu or 89Zr were the ones used more frequently), which brought an attention on the positron emitter 52Mn isotope (t1/2=5.59 days). On the other hand Mn(II) complexes have been intensively studied recently as monoaquated chelates of Mn(II) are considered safer alternatives to Gd(III)-based contrast agents (GBCA’s) in magnetic resonance imaging (MRI). Therefore the use of Mn(II) complexes also offers the possibility of “marrying” these two diagnostic modalities. In MRI new, safer alternatives are needed, since Nephrogenic Systemic Fibrosis (NSF) in renal patients has been linked to the toxic effect of Gd(III) ion released during dissociation of the applied CA (Gd(III) complexes). Ten years later, it was also confirmed that injected Gd(III) can accumulate in patients with healthy kidney function, while Gd(III) chelates excreted from the body increase Gd(III) concentrations in surface water (“gadolinium anomaly”). Related to this research topic, our current paper summarizes the most suitable chelators designed for complexation of Mn(II) ions. Bifunctional ligands developed for Mn(II) complexation and intelligent/responsive Mn(II)-based probes were also reviewed, furthermore, information on the possible biological vector molecules was also summarized. Based on this information we present examples of the application of vector molecules that have performed outstandingly in in vivo experiments and their 52Mn isotopically labeled conjugates that we have developed and tested using animal models.

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