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.

Basic information

Original name

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

Authors

PAZDEROVÁ, Lucia (203 Czech Republic), Martina BENEŠOVÁ (203 Czech Republic), Jana HAVLÍČKOVÁ (203 Czech Republic), Margareta VOJTÍČKOVÁ (203 Czech Republic), Jan KOTEK (203 Czech Republic), Přemysl LUBAL (203 Czech Republic, belonging to the institution), Martin ULLRICH (276 Germany), Martin WALTHER (276 Germany), Sabine SCHULZE (276 Germany), Christin NEUBER (276 Germany), Stefan RAMMELT (276 Germany), Hans-Jürgen PIETZSCH (276 Germany), Jens PIETZSCH (276 Germany), Vojtěch KUBÍČEK (203 Czech Republic, guarantor) and Petr HERMANN (203 Czech Republic)

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10400 1.4 Chemical sciences

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 4.000

RIV identification code

RIV/00216224:14310/22:00125995

Organization unit

Faculty of Science

DOI

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

UT WoS

000807023900001

Keywords in English

macrocyclic complexes; cyclam derivatives; kinetic inertness; Equilibrium studies

Abstract

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.

Links

LTC20044, research and development project

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

Investor: Ministry of Education, Youth and Sports of the CR, INTER-COST

MUNI/A/1539/2021, interní kód MU

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

Investor: Masaryk University

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 and 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, vol. 51, No 24, p. 9541-9555. ISSN 1477-9226. Available from: 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 and 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, vol.~51, No~24, p.~9541-9555. ISSN~1477-9226. Available from: https://dx.doi.org/10.1039/D2DT01172G.

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