In Vitro and In Vivo Characterization of a Novel Bifunctionalized Water-Soluble Dithia-Bisphosphine ^99mTc Complex

Abstract

The novel tetradentate, bifunctional chelating agent (BFCA) Dithia(bishydroxymethyl)bisphosphine (P 2 S 2 -COOH) was synthesized. The water-soluble ligand P 2 S 2 -COOH produces a Tc-99m-complex of radiochemical purity >95% at a BFCA concentration of 10~5 M by direct reduction of [TcO.,]" in presence of the ligand with Sn 2+ or by irans-chelation using "Tc-gluconate. HPLC analyses indicate the formation of a single species. The chromatographic retention time for this new technetium BFCA is similar to the correponding Re(V)-BFCA, suggesting the identical chemical structure on the tracer level. The "Tc-P 2 S 2 -COOH complex is stable over a wide range of pH (3-9) for >24 h. Biodistribution studies in the normal mouse model exhibited a fast clearance of the radioactivity from the bloodstream and excretion of the complex through the renal and the hepatobiliary pathways. The results of this investigations suggest that the phosphinethioether P 2 S 2 -chelate system is a possible alternative to the other bifunctional systems for the radiolabeling of site specific biomolecules with "Te and 186/188 R e .

Synthesis, Characterization, and Labeling with 99mTc/188Re of Peptide Conjugates Containing a Dithia-bisphosphine Chelating Agent

“…In the preconjugation labeling approach (Scheme 4), the 99m Tc-P 2 S 2 -COOH complex was first prepared according to our previously reported procedure. 34,35 The formation of the 99m Tc-P 2 S 2 -COOH complex was confirmed by HPLC. The carboxylic functionality was activated by formation of its pentafluorophenol (PFP) ester.…”

“…33,34 The complexes of Tc-99m with the new chelating framework demonstrate excellent in vitro and in vivo stability and desirable clearance and excretion properties (from the blood stream). 29,32,34,35 This study describes an effective approach for synthesizing P 2 S 2 conjugated peptides to produce products in which the two hydroxymethylene phosphine (HMP) groups are not oxidized by convenient routes (e.g., automated SPPS is exceptionally challenging). For example, the HMP groups are oxidized when P 2 S 2 conjugated peptides synthesized by SPPS are cleaved from the resin by TFA.…”

Characterization of complexation reactions of mono- and bidentate-hydroxymethyl phosphine ligands with the organometallic 99mTc(I)(OH2)3(CO)3 + synthon

“…Multidentate ligands containing the water soluble, oxidatively stable hydroxymethylene phosphine groups have also been shown to produce 99m Tc and 188 Re complexes with high yields and in vitro and in vivo stability [32][33][34][35][36][37][38][39][40][41][42]. The synergistic interactions of the sigma donor and M → Pπ backbonding characteristics of phosphines results in strong Tc-and Re-phosphine bonds that have optimal stability, even under in vivo conditions [32][33][34][35][36][37][38][39][40][41][42].…”

New Vistas in Chemistry and Applications of Primary Phosphines

“…The ease with which P-H bonds in primary phosphines can be converted to P-C bonds, as shown in Schemes 9 and 10, demonstrates the importance of primary phosphines in the design and development of novel organophosphorus compounds. In particular, functionalized hydroxymethyl phosphines have become ubiquitous in the development of watersoluble transition metal/organometallic compounds for potential applications in biphasic aqueous-organic catalysis and also in transition metal based pharmaceutical development [53][54][55][56][57][58][59][60][61][62]. Extensive investigations on the coordination chemistry of hydroxymethyl phosphines have demonstrated unique stereospecific and kinetic propensity of this class of water-soluble phosphines [53][54][55][56][57][58][59][60][61][62].…”

“…Representative examples outlined in Fig. 4, depict bidentate and multidentate coordination modes and the unique kinetic propensity to stabilize various oxidation states of metal centers, such as Re(V), Rh(III), Pt(II) and Au(I), in aqueous media [53][54][55][56][57][58][59][60][61][62]. Therefore, the importance of functionalized primary phosphines in the development of multidentate water-soluble phosphines cannot be overemphasized.…”