Imidazole-Based [2 + 1] Re(I)/^99mTc(I) Complexes as Isostructural Nuclear and Optical Probes

The synthesis, stability, and photophysical properties of [2 + 1] Re­(I)/Tc­(I) complexes derived from bipyridine and a series of imidazole derivatives were investigated as a means of identifying complexes suitable for creating targeted isostructural optical/nuclear molecular imaging probes. To prepare the desired complexes, [Re­(CO)₃­(H₂O)₃]Br was combined with 2,2′-bipyridine (bipy) to give [Re­(CO)₃­(bipy)­Br], which in turn was converted to the desired complexes by treatment with functionalized imidazoles, yielding crystal structures of two new Re complexes. The corresponding ^99mTc complexes [^99mTc­(CO)₃­(bipy)­(L)]⁺ (L = imidazole derivatives) were prepared by combining [^99mTc­(CO)₃­(bipy)­(H₂O)]Cl with the same series of ligands and heating at 40 or 60 °C for 30 min. Quantitative transformation to the final products was confirmed in all cases by HPLC, and the nature of the complexes was verified by comparison to the authentic Re standards. Incubation in saline and plasma, and amino acid challenge experiments showed that N-substituted imidazole derivatives, bearing electron donating groups, exhibited superior stability to analogous metal complexes derived from less basic ligands. Imaging studies in mice revealed that with the appropriate choice of monodentate ligand, it is possible to prepare robust [2 + 1] Tc complexes that can be used as the basis for preparing targeted isostructural optical and nuclear probes

Isostructural Nuclear and Luminescent Probes Derived From Stabilized [2 + 1] Rhenium(I)/Technetium(I) Organometallic Complexes

A convenient method to prepare ^99mTc analogues of a class of rhenium­(I) luminophores was developed, creating isostructural pairs of nuclear and optical probes. A two-step procedure and a new one-pot procedure were used to produce a series of [2 + 1] complexes of the type [Tc­(CO)₃(bipy)­L]⁺ in greater than 80% yield. The plasma stability of the reported compounds was evaluated, where the basicity of the monodentate pyridine type ligand (L) has a significant impact with half-lives ranging from 2 to 20 h. The ability to generate the radioactive complexes makes it possible to quantitate cell uptake of Re luminophores, which was demonstrated in MCF-7 breast cancer cells using ^99mTc analogues of two Re­(I)-based mitochondrial targeting dyes

Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy

The feasibility of developing a single agent that can deliver radioactive iodine and also direct cellular immune function by engaging endogenous antibodies as an antibody-recruiting small molecule (ARM) was determined. A library of new prostate-specific membrane antigen (PSMA)-binding ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP) groups and iodine were synthesized and screened in vitro and in vivo. A lead compound (<b>9b</b>) showed high affinity for PSMA and the ability to bind anti-DNP antibodies. Biodistribution studies of the iodine-125 analogue showed 3% ID/g in LNCaP xenograft tumors at 1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of 10:1 and 44:1, respectively. The radiolabeled analogue was bound and internalized by LNCaP cells, with both functions blocked using a known PSMA inhibitor. A second candidate showed high tumor uptake (>10% ID/g) but had minimal binding to anti-DNP antibodies. The compounds reported represent the first examples of small molecules developed specifically for combination immunotherapy and radiotherapy for prostate cancer