Biodistribution of the Multidentate Hydroxypyridinonate Ligand [¹⁴C]‐3,4,3‐LI(1,2‐HOPO), a Potent Actinide Decorporation Agent

Abstract

The pharmacokinetics and biodistribution of the (14) C-labeled actinide decorporation agent 3,4,3-LI(1,2-HOPO) were investigated in young adult Swiss Webster mice and Sprague Dawley rats, after intravenous, intraperitoneal, and oral dose administration. In all routes investigated, the radiolabeled compound was rapidly distributed to various tissues and organs of the body. In mice, the 24 h fecal elimination profiles suggested that the biliary route is the predominant route of elimination. In contrast, lower fecal excretion levels were observed in rats. Tissue uptake and retention of the compound did not differ significantly between sexes although some differences were observed in the excretion patterns over time. The male mice eliminated a greater percentage of (14) C through the renal pathway than the female mice after receiving an intravenous or intraperitoneal dose, while the opposite trend was seen in rats that received an intravenous dose. Metabolite profiling performed on selected rat samples demonstrated that a putative major metabolite of [(14) C]-3,4,3-LI(1,2-HOPO) is formed, accounting for approximately 10% of an administered oral dose. Finally, to improve its oral bioavailability, 3,4,3-LI(1,2-HOPO) was coformulated with a proprietary permeability enhancer, leading to a notable increase in oral bioavailability of the compound.

From early prophylaxis to delayed treatment: Establishing the plutonium decorporation activity window of hydroxypyridinonate chelating agents

“…While the 238 Pu complexes formed with 3,4,3-LI(1,2-HOPO) or DTPA undergo relatively fast clearance and are fully expelled from the body within 24 hours [15], it has been suggested that the sustained excretion enhancement profiles in treated animals are due to intracellular uptake of the ligands and delayed clearance [25]. The pharmacokinetics and biodistribution profile of the 14 C-labeled 3,4,3-LI(1,2-HOPO) were recently characterized in the young Swiss-Webster mouse model used here [26]. After parenteral injection, the radiolabeled compound was rapidly distributed into high vascular tissues, and highest kidney and liver concentrations were seen as early as 1-hour post-administration.…”

“…Those differences have been discussed previously and are presumably based on respective ligand and actinide-complex physico-chemical parameters such as solubility, lipophilicity, and ionization constants [15, 20, 21]. In addition, the biliary pathway is the main mode of elimination for 3,4,3-LI(1,2-HOPO) in mice, as demonstrated by high accumulation of 14 C-labeled 3,4,3-LI(1,2-HOPO) in the feces after either parenteral or oral administration [26]. It is therefore likely that the radionuclide excretion path is ligand-driven.…”

Electronic structure theory to decipher the chemical bonding in actinide systems

“…The areas of study have expanded in recent years with applications in the fields of nuclear toxicology [3][4][5][6], cancer therapy (e.g., the radioisotope 225 Ac of actinium is an alpha emitter useful for targeted radiotherapy [7]), analytical chemistry [8], and in basic research in structural chemistry and reaction mechanisms [9]. All these applications have in common the need to develop pre-organised chelating agents.…”

Improving Decorporation Efficacy of DTPA and HOPO Using Chitosan/TPP Nanoparticles: Preparation, Characterization and Release Testing

“…is a wider spectrum actinide decorporation agent and can chelate with plutonium (Pu), americium (Am), curium(Cm), uranium (U) or neptunium (Np) ions to form stable complexes at physiological pH [12][13][14][15][16][17][18] . This novel decorporation agent is currently undergoing pre-clinical development [18] .…”

“…is a wider spectrum actinide decorporation agent and can chelate with plutonium (Pu), americium (Am), curium(Cm), uranium (U) or neptunium (Np) ions to form stable complexes at physiological pH [12][13][14][15][16][17][18] . This novel decorporation agent is currently undergoing pre-clinical development [18] . Moreover, this promising compound has higher potency and can chelate more internally deposited radionuclides than the commonly used actinide decorporation agent DTPA [14][15][16]18] .…”