Preparation and Biological Characterization of Isomeric ¹⁸⁸Re(V) Oxocomplexes with Tetradentate S₄ Ligands Derived from meso-Dimercaptosuccinic Acid for Labeling of Biomolecules

Abstract

A new type of tetradentate S4 ligand has been synthesized by bridging two molecules of meso-2,3-dimercaptosuccinic acid for stable binding and easy conjugation of rhenium-188 to tumor targeting structures. The stereoisomeric tetrathiolato S4 ligands form very robust anionic five-coordinated oxorhenium(V) and oxotechnetium(V) complexes. Two routes for the preparation of the (188)Re(V) oxocomplexes with (iBu)2N(O)C-C(SH)C(SH)C(O)NH(CH2)3NH(CH2)3NHC(O)C(SH)C(SH)C(O)N(iBu)2 (ligand 1) and its hydrophilic crown ether derivative (ligand 2) were tested and optimized. Several isomers were separated by HPLC from the preparation solutions and characterized in vitro and in vivo. The identity of the species obtained was determined by comparison with the HPLC profiles of reference (185/187)Re analogues and (99/99m)Tc complexes which were characterized by ESI-MS. All of them were absolutely stable in rat and human plasma solutions. Challenge experiments with cysteine corroborated the high inertness of the isomers toward ligand exchange reactions. Various in vivo samples, taken off at different times from blood, intestine, and urine of rats, confirmed the high in vivo stability of the (188)Re-S4 complexes. Biodistribution studies using male Wistar rats were performed and exhibited a high uptake and fast clearance from the liver of the more lipophilic cis and trans isomers of complex I (log P(o/w) between 1.5 and 1.7), whereas the isomers of the hydrophilic complex II (log P(o/w) about -1.75) were rapidly excreted via the renal and the hepatobiliary pathway. The low level of activity in the stomach confirms good in vivo stability. Thus, these new (188)Re-S4 complexes fulfill the requirements for a stable and high specific activity labeling of biomolecules with rhenium-188.

Very stable 188Re-S4 chelates for labelling biomolecules

“…Because the redoxp otential of rhenium is lowerthanthatoftechnetium, perrhenate is moredifficult to reduce thanpertechnetate, andthe prepared 188 Re complexesare more easily re-oxidised.T oi mprovet he stability of the complexest owardr e-oxidation,w e developed atetradentate S 4 ligandbybridging twoD MSA molecules( 4). Thec orresponding 188 Re-S 4 complexesare easily to preparei nh igh yields by ak it formulation andare stable toward ligandexchange (cysteine,g lutathione) ( 10). Here we present studies concerning the preparation of these novelc omplexes at therapeutic relevant radioactive concentrationsand their in vitro and in vivo stability.T he results arec omparedw ith 188 Re-MAG 3 and 188 Re-DMSA preparations performed at the samer adioactivity level.The applicability of the MAG 3 chelateunit for astablelabelling with rhenium-188 is differentlydescribedinthe literature (3,6).…”

Quantitative Structure Property Relationship of log<i>P</i> for Radiopharmaceutical Technetium and Rhenium Complexes by using Molecular Dynamics Calculations

“…Input coordinates were obtained from X-ray crystal structure data contained in the Cambridge Crystallographic Data Centre (CCDC) [14][15][16]20]. The constant values of force field parameters were adjusted until an optimal agreement between calculated and observed structures was obtained throughout the entire range of available structures.…”

“…Among tumor-seeking agents, the metal-DMSA complex, Re to biomolecules and (ii) the determination of physicochemical parameters such as solubility, dissociative partition coefficients, lipophilicity and protein binding. Since the lipophilicity of radiotracer complexes is well correlated to the biodistribution [15,16], it is of great interest to develop a novel estimation method of logP for radiotracers.…”

Synthesis of the first radiolabeled 188Re N‐heterocyclic carbene complex and initial studies on its potential use in radiopharmaceutical applications

“…8–11 Specifically, 186/188 Re-hydroxylethylene diphosphonate complexes are currently being used as palliative therapeutics for bone metastases, 11,12 and 186/188 Re-complexes with thiolate-functionalities and amine/amide-functionalities can be used for the treatment of hepatocellular carcinoma (Figure 1(A–C)). 10,13–16 Tetradentate N 3 S type complexes (Figure 1(D)) have been especially popular as chelate scaffolds for radiolabeled antibodies. 17,18 In addition, various organometallic rhenium(I)-tricarbonyl complexes have also proven suitable chelation architectures (Figure 1(E)).…”

“…Several 186 Re‐based or 188 Re‐based radiopharmaceuticals have been tested in preclinical studies, and some of them have been successfully translated to the clinic . Specifically, 186/188 Re‐hydroxylethylene diphosphonate complexes are currently being used as palliative therapeutics for bone metastases, and 186/188 Re‐complexes with thiolate‐functionalities and amine/amide‐functionalities can be used for the treatment of hepatocellular carcinoma (Figure (A–C)) . Tetradentate N 3 S type complexes (Figure (D)) have been especially popular as chelate scaffolds for radiolabeled antibodies .…”