Gallium(III) complexes
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Four gallium(III) complexes, [Ga(ClQ)3]⋅MeOH (1 - MeOH), [Ga(ClQ)3] (1), [Ga(BrQ)3] (2), [Ga(dIQ)3] (3) and [Ga(CQ)3] (4), were prepared (H-ClQ = 5-chloro-8-quinolinol, H-BrQ = 7-bromo-8-quinolinol, H-dIQ = 5,7-diiodo-8-quinolinol, H-CQ = 5-chloro-7-iodo-8-quinolinol) and characterised by elemental analysis, IR and NMR spectroscopy. Single crystal structure analysis of 1 - MeOH confirmed that the complex has a molecular structure with gallium(III) metal ion coordinated in mer-fashion by N- and O-donor atoms of three ClQ ligands. Stability of all complexes in DMSO was proved by 1H NMR spectroscopy. The in vitro antiproliferative activity of 1 was evaluated against the A2780, MBA-MB-231 and HCT116 cell lines. Complex 1 displays higher antiproliferative activity (IC50 values in the range 2.1-6 μm) compared to the ClQ ligand and cisplatin; and a significant selective antiproliferative potency (IC50 = 136 μm, for normal MRC5pd30 cell line). Radical scavenging experiments revealed that complex 1 exhibits the highest antioxidant activity of the prepared complexes as well as the ligands.
- MeSH
- chinoliny chemická syntéza farmakologie MeSH
- galium chemie MeSH
- komplexní sloučeniny chemická syntéza farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza farmakologie MeSH
- scavengery volných radikálů chemická syntéza farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)M(BP) (L1). The ligands were labeled with (68)Ga(III) and were evaluated in in vitro binding studies to hydroxyapatite (HA) as well as to human serum albumin. The compounds were finally compared in in vivo PET and ex vivo organ distribution studies in small animals over 6h. Binding studies revealed a consistent affinity of both bisphosphonate tracers to HA. Small animal PET and ex vivo organ distribution studies showed longer blood retention of [(68)Ga]L1. [(68)Ga]BPAMD is initially more efficiently bound to the bone but skeletal accumulation of the modified compound and [(68)Ga]BPAMD equalized at 6h p.i. Ratios of femur epiphyseal plate to ordinary bone showed to be more favorable for [(68)Ga]L1 than for [(68)Ga]BPAMD due to the longer circulation time of the new tracer. Thus, the chemical modification of BPAMD toward an albumin-binding bisphosphonate, L1, resulted in a novel PET tracer which conserves advantages of both functional groups within one and the same molecule. The properties of this new diagnostic tracer are expected to be preserved in (177)Lu therapeutic agent with the same ligand (a theranostic pair).
- MeSH
- adsorpce MeSH
- bisfosfonáty chemie metabolismus farmakokinetika MeSH
- heterocyklické sloučeniny monocyklické chemie MeSH
- hydroxyapatit chemie MeSH
- kosti a kostní tkáň diagnostické zobrazování metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- potkani Wistar MeSH
- pozitronová emisní tomografie MeSH
- radioizotopy galia MeSH
- sérový albumin metabolismus MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT.
- MeSH
- bisfosfonáty * chemie farmakokinetika farmakologie MeSH
- femur metabolismus radiografie MeSH
- galium * chemie farmakokinetika farmakologie MeSH
- kontrastní látky * chemie farmakokinetika farmakologie MeSH
- krysa rodu rattus MeSH
- pozitronová emisní tomografie metody MeSH
- radioaktivní indikátory * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
