Technetium(I) Complexes of Bathophenanthrolinedisulfonic Acid

Bathophenanthrolinedisulfonate (BPS) complexes of technetium­(I) of the type [Tc­(CO)₃(BPS)­(L)]^<i>n</i> (L = imidazole derivatives) were synthesized and evaluated both in vitro and in vivo. [^99mTc­(CO)₃(BPS)­(MeIm)]⁻ (MeIm = 1-methyl-1<i>H</i>-imidazole) was prepared in near-quantitative yield using a convenient two-step, one-pot labeling procedure. A targeted analogue capable of binding regions of calcium turnover associated with bone metabolism was also prepared. Here, a bisphosphonate was linked to the metal through an imidazole ligand to give [^99mTc­(CO)₃(BPS)­(ImAln)]^2– (ImAln = an imidazole–alendronate ligand) in high yield. The technetium­(I) complexes were stable in vitro, and in biodistribution studies, [^99mTc­(CO)₃(BPS)­(ImAln)]^2– exhibited rapid clearance from nontarget tissues and significant accumulation in the shoulder (7.9 ± 0.2% ID/g) and knees (15.1 ± 0.9% ID/g) by 6 h, with the residence time in the skeleton reaching 24 h. A rhenium analogue, which is luminescent and has the same structure, was also prepared and used for fluorescence labeling of cells in vitro. The data reported demonstrate the potential of this class of compounds for use in creating isostructural optical and nuclear probes

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

A Bone-Seeking <i>trans</i>-Cyclooctene for Pretargeting and Bioorthogonal Chemistry: A Proof of Concept Study Using ^99mTc- and ¹⁷⁷Lu-Labeled Tetrazines

A high yield synthesis of a novel, small molecule, bisphosphonate-modified <i>trans</i>-cyclooctene (TCO-BP, <b>2</b>) that binds to regions of active bone metabolism and captures functionalized tetrazines in vivo, via the bioorthogonal inverse electron demand Diels–Alder (IEDDA) cycloaddition, was developed. A ^99mTc-labeled derivative of <b>2</b> demonstrated selective localization to shoulder and knee joints in a biodistribution study in normal mice. Compound <b>2</b> reacted rapidly with a ¹⁷⁷Lu-labeled tetrazine in vitro, and pretargeting experiments in mice, using <b>2</b> and the ¹⁷⁷Lu-labeled tetrazine, yielded high activity concentrations in shoulder and knee joints, with minimal uptake in other tissues. Pretargeting experiments with <b>2</b> and a novel ^99mTc-labeled tetrazine also produced high activity concentrations in the knees and shoulders. Critically, both radiolabeled tetrazines showed negligible uptake in the skeleton and joints when administered in the absence of <b>2</b>. Compound <b>2</b> can be utilized to target functionalized tetrazines to bone and represents a convenient reagent to test novel tetrazines for use with in vivo bioorthogonal pretargeting strategies