Monooxorhenium(V) complexes with 222-N2S2 MAMA ligands for bifunctional chelator agents: Syntheses and preliminary in vivo evaluation

Abstract

Introduction Targeted radiotherapy using the bifunctional chelate approach with 186/188Re(V) is challenging because of the susceptibility of monooxorhenium(V)-based complexes to oxidize in vivo at high dilution. A monoamine-monoamide dithiol (MAMA)-based bifunctional chelating agent was evaluated with both rhenium and technetium to determine its utility for in vivo applications. Methods A 222-MAMA chelator, 222-MAMA(N-6-Ahx-OEt) bifunctional chelator, and 222- MAMA(N-6-Ahx-BBN(7-14)NH2) were synthesized, complexed with rhenium, radiolabeled with 99mTc and 186Re (carrier added and no carrier added), and evaluated in initial biological distribution studies. Results An IC50 value of 2.0 ± 0.7 nM for natReO-222-MAMA(N-6-Ahx-BBN(7-14)NH2) compared to [125I]-Tyr4-BBN(NH2) was determined through competitive cell binding assays with PC-3 tumor cells. In vivo evaluation of the no-carrier added 99mTc-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed little gastric uptake and blockable pancreatic uptake in normal mice. Conclusions The 186ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed stability in biological media, which indicates that the 222-N2S2 chelator is appropriate for chelating 186/188Re in radiopharmaceuticals involving peptides. Additionally, the in vitro cell studies showed that the ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex (macroscopically) bound to PC3-tumor cell surface receptors with high affinity. The 99mTc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting.

Bifunctional chelators for radiorhenium: past, present and future outlook

“…33 Rhenium has two medically relevant isotopes ( 186 Re and 188 Re), the nuclear properties of which are summarised in Table 1. 20,23,[33][34][35] They are β − -particle emitting isotopes which each have different half-lives and particle energies, making them suitable for different tissue ranges in the body. [34][35][36] The shorter tissue penetration range of 186 Re means it is suitable for the targeting of small tumours while 188 Re is appropriate for much larger, heterogeneous masses for which deep tissue penetration is required.…”

“…20,23,[33][34][35] They are β − -particle emitting isotopes which each have different half-lives and particle energies, making them suitable for different tissue ranges in the body. [34][35][36] The shorter tissue penetration range of 186 Re means it is suitable for the targeting of small tumours while 188 Re is appropriate for much larger, heterogeneous masses for which deep tissue penetration is required. 32,34,35 Additionally, both rhenium isotopes also co-emit γ-radiation, which allows for in vivo imaging of 186/188 Re-labelled biomolecules as well as for dosimetry calculations.…”

Bulk production and evaluation of high specific activity 186gRe for cancer therapy using enriched 186WO3 targets in a proton beam

“…This production study was thus carried out using enriched 186 WO 3 targets that allow for easy chemical processing, 186g Re isolation and enriched target material recovery. Isolated 186g Re product was used for the synthesis and preliminary in vivo evaluation of 186g Re-monooxorhenium(V) complexes, which was published as well [30].…”

“…This demonstrates the utility of our high specific activity 186g ReO 4 final product for use in radiolabeling studies. Additionally, 186g Re from this production was used to successfully radiolabel N 2 S 2 -BBN [30].…”

Zn Complex of Diaminedithiol Tetradentate Ligand as a Stable Precursor for 99mTc-Labeled Compounds

“…A tetradentate chelating agent containing two amines and two thiol groups, referred to as a diaminedithiol (DADT) or a bis(amino ethanethiol: BAT), forms a neutral, lipophilic, and stable complex with the pentavalent oxo-Tc and oxo-Re (TcO 3+ and ReO 3+ ) [1,2]. Such characteristics render DADT attractive as a coordination molecule for 99m Tc-and 186/188 Re-labeled compounds [3][4][5][6]. A presentative structure of DADT ligand is shown in Scheme 1, compound 6 (N 2 S 2 ).…”