Cyclam with a phosphinate-bis(phosphonate) pendant arm is a
bone-targeting carrier of copper radionuclides

J 2022

Cyclam with a phosphinate-bis(phosphonate) pendant arm is a bone-targeting carrier of copper radionuclides

PAZDEROVÁ, Lucia, Martina BENEŠOVÁ, Jana HAVLÍČKOVÁ, Margareta VOJTÍČKOVÁ, Jan KOTEK et. al.

Základní údaje

Originální název

Cyclam with a phosphinate-bis(phosphonate) pendant arm is a bone-targeting carrier of copper radionuclides

Autoři

PAZDEROVÁ, Lucia (203 Česká republika), Martina BENEŠOVÁ (203 Česká republika), Jana HAVLÍČKOVÁ (203 Česká republika), Margareta VOJTÍČKOVÁ (203 Česká republika), Jan KOTEK (203 Česká republika), Přemysl LUBAL (203 Česká republika, domácí), Martin ULLRICH (276 Německo), Martin WALTHER (276 Německo), Sabine SCHULZE (276 Německo), Christin NEUBER (276 Německo), Stefan RAMMELT (276 Německo), Hans-Jürgen PIETZSCH (276 Německo), Jens PIETZSCH (276 Německo), Vojtěch KUBÍČEK (203 Česká republika, garant) a Petr HERMANN (203 Česká republika)

Vydání

Dalton Trans, Royal Society of Chemistry, 2022, 1477-9226

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10400 1.4 Chemical sciences

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.000

Kód RIV

RIV/00216224:14310/22:00125995

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1039/D2DT01172G

UT WoS

000807023900001

Klíčová slova anglicky

macrocyclic complexes; cyclam derivatives; kinetic inertness; Equilibrium studies

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 7. 12. 2022 14:47, Mgr. Marie Šípková, DiS.

Anotace

V originále

Ligands combining a bis(phosphonate) group with a macrocycle function as metal isotope carriers for radionuclide-based imaging and for treating bone metastases associated with several cancers. However, bis(phosphonate) pendant arms often slow down complex formation and decrease radiochemical yields. Nevertheless, their negative effect on complexation rates may be mitigated by using a suitable spacer between bis(phosphonate) and the macrocycle. To demonstrate the potential of bis(phosphonate) bearing macrocyclic ligands as a copper radioisotope carrier, we report the synthesis of a new cyclam derivative bearing a phosphinate-bis(phosphonate) pendant (H5te1PBP). The ligand showed a high selectivity to CuII over ZnII and NiII ions, and the bis(phosphonate) group was not coordinated in the CuII complex, strongly interacting with other metal ions in solution. The CuII complex formed quickly, in 1 s, at pH 5 and at a millimolar scale. The complexation rates significantly differed under a ligand or metal ion excess due to the formation of reaction intermediates differing in their metal-to-ligand ratio and protonation state, respectively. The CuII-te1PBP complex also showed a high resistance to acid-assisted hydrolysis (t1/2 2.7 h; 1 M HClO4, 25 °C) and was effectively adsorbed on the hydroxyapatite surface. H5te1PBP radiolabeling with [64Cu]CuCl2 was fast and efficient, with specific activities of approximately 30 GBq 64Cu per 1 μmol of ligand (pH 5.5, room temperature, 30 min). In a pilot experiment, we further demonstrated the excellent suitability of [64Cu]CuII-te1PBP for imaging active bone compartments by dedicated small animal PET/CT in healthy mice and subsequently in a rat femoral defect model, in direct comparison with [18F]fluoride. Moreover, [64Cu]CuII-te1PBP showed a higher uptake in critical bone defect regions. Therefore, our study highlights the potential of [64Cu]CuII-te1PBP as a PET radiotracer for evaluating bone healing in preclinical and clinical settings with a diagnostic value similar to that of [18F]fluoride, albeit with a longer half-life (12.7 h) than 18F (1.8 h), thereby enabling extended observation times.

Návaznosti

LTC20044, projekt VaV

Název: Thermodynamic and kinetic investigations of metal complexes of polydentate ligands for biomedical, analytical and industrial applications (Akronym: NECTAR_COST)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Thermodynamic and kinetic investigations of metal complexes of polydentate ligands for biomedical, analytical and industrial applications, INTER-COST

MUNI/A/1539/2021, interní kód MU

Název: Vývoj metod a instrumentace pro analýzu biologicky významných látek 2022

Investor: Masarykova univerzita, Vývoj metod a instrumentace pro analýzu biologicky významných látek 2022

Citovat

PAZDEROVÁ, Lucia, Martina BENEŠOVÁ, Jana HAVLÍČKOVÁ, Margareta VOJTÍČKOVÁ, Jan KOTEK, Přemysl LUBAL, Martin ULLRICH, Martin WALTHER, Sabine SCHULZE, Christin NEUBER, Stefan RAMMELT, Hans-Jürgen PIETZSCH, Jens PIETZSCH, Vojtěch KUBÍČEK a Petr HERMANN. Cyclam with a phosphinate-bis(phosphonate) pendant arm is a bone-targeting carrier of copper radionuclides. Dalton Trans. Royal Society of Chemistry, 2022, roč. 51, č. 24, s. 9541-9555. ISSN 1477-9226. Dostupné z: https://dx.doi.org/10.1039/D2DT01172G.

@article{1860064,
   author = {Pazderová, Lucia and Benešová, Martina and Havlíčková, Jana and Vojtíčková, Margareta and Kotek, Jan and Lubal, Přemysl and Ullrich, Martin and Walther, Martin and Schulze, Sabine and Neuber, Christin and Rammelt, Stefan and Pietzsch, HansandJürgen and Pietzsch, Jens and Kubíček, Vojtěch and Hermann, Petr},
   article_number = {24},
   doi = {http://dx.doi.org/10.1039/D2DT01172G},
   keywords = {macrocyclic complexes; cyclam derivatives; kinetic inertness; Equilibrium studies},
   language = {eng},
   issn = {1477-9226},
   journal = {Dalton Trans},
   title = {Cyclam with a phosphinate-bis(phosphonate) pendant arm is a bone-targeting carrier of copper radionuclides},
   url = {https://pubs.rsc.org/en/content/articlelanding/2022/DT/D2DT01172G},
   volume = {51},
   year = {2022}
}

TY  - JOUR
ID  - 1860064
AU  - Pazderová, Lucia - Benešová, Martina - Havlíčková, Jana - Vojtíčková, Margareta - Kotek, Jan - Lubal, Přemysl - Ullrich, Martin - Walther, Martin - Schulze, Sabine - Neuber, Christin - Rammelt, Stefan - Pietzsch, Hans-Jürgen - Pietzsch, Jens - Kubíček, Vojtěch - Hermann, Petr
PY  - 2022
TI  - Cyclam with a phosphinate-bis(phosphonate) pendant arm is a bone-targeting carrier of copper radionuclides
JF  - Dalton Trans
VL  - 51
IS  - 24
SP  - 9541-9555
EP  - 9541-9555
PB  - Royal Society of Chemistry
SN  - 14779226
KW  - macrocyclic complexes
KW  - cyclam derivatives
KW  - kinetic inertness
KW  - Equilibrium studies
UR  - https://pubs.rsc.org/en/content/articlelanding/2022/DT/D2DT01172G
N2  - Ligands combining a bis(phosphonate) group with a macrocycle function as metal isotope carriers for radionuclide-based imaging and for treating bone metastases associated with several cancers. However, bis(phosphonate) pendant arms often slow down complex formation and decrease radiochemical yields. Nevertheless, their negative effect on complexation rates may be mitigated by using a suitable spacer between bis(phosphonate) and the macrocycle. To demonstrate the potential of bis(phosphonate) bearing macrocyclic ligands as a copper radioisotope carrier, we report the synthesis of a new cyclam derivative bearing a phosphinate-bis(phosphonate) pendant (H5te1PBP). The ligand showed a high selectivity to CuII over ZnII and NiII ions, and the bis(phosphonate) group was not coordinated in the CuII complex, strongly interacting with other metal ions in solution. The CuII complex formed quickly, in 1 s, at pH 5 and at a millimolar scale. The complexation rates significantly differed under a ligand or metal ion excess due to the formation of reaction intermediates differing in their metal-to-ligand ratio and protonation state, respectively. The CuII-te1PBP complex also showed a high resistance to acid-assisted hydrolysis (t1/2 2.7 h; 1 M HClO4, 25 °C) and was effectively adsorbed on the hydroxyapatite surface. H5te1PBP radiolabeling with [64Cu]CuCl2 was fast and efficient, with specific activities of approximately 30 GBq 64Cu per 1 μmol of ligand (pH 5.5, room temperature, 30 min). In a pilot experiment, we further demonstrated the excellent suitability of [64Cu]CuII-te1PBP for imaging active bone compartments by dedicated small animal PET/CT in healthy mice and subsequently in a rat femoral defect model, in direct comparison with [18F]fluoride. Moreover, [64Cu]CuII-te1PBP showed a higher uptake in critical bone defect regions. Therefore, our study highlights the potential of [64Cu]CuII-te1PBP as a PET radiotracer for evaluating bone healing in preclinical and clinical settings with a diagnostic value similar to that of [18F]fluoride, albeit with a longer half-life (12.7 h) than 18F (1.8 h), thereby enabling extended observation times.
ER  -

PAZDEROVÁ, Lucia, Martina BENEŠOVÁ, Jana HAVLÍČKOVÁ, Margareta VOJTÍČKOVÁ, Jan KOTEK, Přemysl LUBAL, Martin ULLRICH, Martin WALTHER, Sabine SCHULZE, Christin NEUBER, Stefan RAMMELT, Hans-Jürgen PIETZSCH, Jens PIETZSCH, Vojtěch KUBÍČEK a Petr HERMANN. Cyclam with a phosphinate-bis(phosphonate) pendant arm is a bone-targeting carrier of copper radionuclides. \textit{Dalton Trans}. Royal Society of Chemistry, 2022, roč.~51, č.~24, s.~9541-9555. ISSN~1477-9226. Dostupné z: https://dx.doi.org/10.1039/D2DT01172G.

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