Premium
A Cyclen‐Based Tetraphosphinate Chelator for the Preparation of Radiolabeled Tetrameric Bioconjugates
Author(s) -
Šimeček Jakub,
Hermann Petr,
Havlíčková Jana,
Herdtweck Eberhardt,
Kapp Tobias G.,
Engelbogen Nils,
Kessler Horst,
Wester HansJürgen,
Notni Johannes
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201300338
Subject(s) - chemistry , dota , cyclen , bioconjugation , chelation , ethylenediaminetetraacetic acid , conjugate , peptide , pegylation , nuclear chemistry , radionuclide therapy , peg ratio , radiochemistry , polyethylene glycol , stereochemistry , combinatorial chemistry , organic chemistry , biochemistry , medicine , mathematical analysis , mathematics , finance , economics , nuclear medicine
The cyclen‐based tetraphosphinate chelator 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrakis[methylene(2‐carboxyethyl)phosphinic acid] (DOTPI) comprises four additional carboxylic acid moieties for bioconjugation. The thermodynamic stability constants (log K ML ) of metal complexes, as determined by potentiometry, were 23.11 for Cu II , 20.0 for Lu III , 19.6 for Y III , and 21.0 for Gd III . DOTPI was functionalized with four cyclo(Arg‐Gly‐Asp‐ D ‐Phe‐Lys) (RGD) peptides through polyethylene glycol (PEG 4 ) linkers. The resulting tetrameric conjugate DOTPI(RGD) 4 was radiolabeled with 177 Lu and 64 Cu and showed improved labeling efficiency compared with 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA). The labeled compounds were fully stable in transchelation challenges against trisodium diethylenetriaminepentaacetate (DTPA) and disodium ethylenediaminetetraacetic acid (ETDA), in phosphate buffered saline (PBS), and human plasma. Integrin α v β 3 affinities of the non‐radioactive Lu III and Cu II complexes of DOTPI(RGD) 4 were 18 times higher (both IC 50 about 70 picomolar) than that of the c(RGDfK) peptide (IC 50 =1.3 nanomolar). Facile access to tetrameric conjugates and the possibility of radiolabeling with therapeutic and diagnostic radionuclides render DOTPI suitable for application in peptide receptor radionuclide imaging (PRRI) and therapy (PRRT).