Target-specific Imaging Agents Research Articles

Nitrido Technetium-99 m Core in Radiopharmaceutical Applications: Four Decades of Research

The knowledge on element 43 (Tc) of the periodic table, built over the years through the contributions given by the close relationship between chemistry and nuclear medicine, allowed the development of new and increasingly effective radiopharmaceuticals useful both as perfusion and target specific imaging agents for SPECT (single photon emission tomography). Among the manifold Tc-compounds, Tc(V) nitrido complexes played a relevant role in the search for new technetium-99m radiopharmaceuticals, providing efficient labeling procedures that can be conveniently exploited for the design and synthesis of agents, also incorporating small organic molecules or peptides having defined structural features. With this work, we present an overview of four decades of research on the chemistry and on the nuclear medicine applications of Tc(V) nitrido complexes.

Multiple Target-Specific Molecular Agents for Detection and Image Analysis of Breast Cancer Characteristics in Mice

Breast cancer is a heterogenetic tumor at the cellular level with multiple factors and components. The inconsistent expression of molecular markers during disease progression reduces the accuracy of diagnosis and efficacy of target-specific therapy. Single target-specific imaging agents can only provide limited tumor information at one time point. In contrast, multiple target-specific imaging agents can increase the accuracy of diagnosis. The aim of this study was to demonstrate the ability of multi-agent imaging to discriminate such differences in single tumor. Mice bearing human cancer cell xenografts were tested to determine individual differences under optimal experimental conditions. Neovasculature agent (RGD peptide), tumor stromal agent (matrix metalloproteinase), and tumor cell markers (epidermal growth factor, Her-2, interleukin 11) imaging agents were labeled with reporters. 18F-Fluorodeoxyglucose was used to evaluate the tumor glucose status. Optical, X-ray, positron emission tomography, and computer tomography imaging modalities were used to determine tumor characteristics. Tumor size and imaging data demonstrated that individual differences exist under optimal experimental conditions. The target-specific agents used in the study bind to human breast cancer cell lines in vitro and xenografts in vivo. The pattern of binding corresponds to that of tumor markers. Multi-agent imaging had complementary effects in tumor detection. Multiple noninvasive imaging agents and modalities are complementary in the interrogation of unique biological information from each individual tumor. Such multi-agent approaches provide methods to study several disease components simultaneously. In addition, the imaging results provide information on disease status at the molecular level.

Re and Tc Complexes with Pyrazolyl-Containing Chelators: from Coordination Chemistry to Target-Specific Delivery of Radioactivity

The design of novel target-specific imaging agents based on 99mTc requires a considerable development of its coordination chemistry. Among all oxidation states available for technetium (-I to VII), the V oxidation state has been the most extensively studied in radiopharmaceutical chemistry, and the majority of the 99mTc-radiopharmaceuticals in clinical use contain the core [99mTc(O)]3+. More recently, the remarkable features of the organometallic precursor fac- [M(CO)3(H2O)3]+ (M = Re, Tc), introduced by Alberto et al., brought renewed interest in the design of innovative lowoxidation 99mTc-based radiopharmaceuticals. Owing to our interest on the design of innovative target-specific radioactive probes, we have been recently involved in the study of the chemistry of [M(O)]3+ and fac-[M(CO)3]+ (M = Re, Tc) with chelators combining a pyrazolyl unit with aliphatic amines and/or carboxylic acids or thioethers. Such research efforts are reviewed herein, where we present an overview of the chemistry, radiochemistry and biological properties of Re and 99mTc complexes anchored by those pyrazolyl-containing chelators with relevance in radiopharmaceutical research. The revised work focuses mainly on tricarbonyl M(I) complexes but M(V) oxocomplexes are also covered. This contribution intends to highlight the potential of pyrazolyl-containing chelators for the labeling of biologically active molecules with 99mTc(I), being presented a variety of examples which include peptides, peptide nucleic acids, inhibitors/substrates of enzymes and DNA-binders.

From Symmetrical to Asymmetrical Nitrido Phosphino-thiol Complexes: A New Class of Neutral Mixed-Ligand 99mTc Compounds as Potential Brain Imaging Agents

A general procedure is presented for the preparation of a new class of nitrido asymmetrical Tc-99m complexes containing two different bidentate ligands bound to the same [Tc(N)]2+ core that could be used to design either essential or target specific imaging agents. This procedure is based on the chemical properties of a new monosubstituted [Tc(N)(R2PS)Cl(PPh3)] species composed of a TcN multiple bond and an ancillary phosphine thiol ligand (R2PSH). This intermediate readily reacts with bidentate mononegative ligands (S--Y) containing soft pi-donor coordinating atoms to give neutral pentacoordinate asymmetrical complexes of the type [Tc(N)(R2PS)(S--Y)]. The ability of several bidentate ligands containing different combination of heteroatoms (S, N, O) to form complexes with the [Tc(N)(R2PS)]+ building block was investigated. It was found that mononegative dithiocarbamate (DTC) or cysteine carboxyl derivate ligands promptly react with the monosubstituted species to form the final mixed compound in high yield. Preliminary biodistribution data in rats of some representative [Tc(N)(R2PS)(DTC)] compounds revealed an interesting initial brain uptake (in the range 0.20 +/- 0.01% ID/g and 0.91 +/- 0.06% ID/g), indicating their ability to cross in and out of the intact BBB. In these complexes the dithiocarbamate, or more generally the bidentate ligand (S--Y), can be designed to carry a functional group or a bioactive molecule, which could be involved in a trapping mechanism to increase brain retention for longer time intervals. These results could be conveniently utilized to devise a new procedure for the production of a novel class of brain perfusion and/or brain receptor imaging agents.

Tc-99m-Labeling of Modified RNA

The synthesis of Tc-99m-labeled, modified RNA is reported. This new class of radiopharmaceuticals is of potential interest as target specific imaging agents. The preparation of N3S-RNA was achieved by coupling protected MAG2-units to amino modified ON's. The N3S-RNA was Tc-99m-labeled with 90–95% radiochemical yield and specific activities of 37MBq/nmol leading to 1:1-Tc-99m-N3S-aptamers.

Synthesis of Tc-99m-labeled, modified RNA

The synthesis of Tc-99m-labeled, modified RNA is reported. This new class of radiopharmaceuticals is of potential interest as target specific imaging agents. The preparation of N 3S-conjugated RNA was achieved by coupling S-protected MAG 2-units to amino modified RNA in solution or on solid support. The starting S-protected MAG 2 building blocks ( 1R-S-CH 2-CO-Gly-Gly- 2R: 1R = Ac, tBu-S; 2R = OH, OSu) were obtained by a simple 4- or 5-step synthesis. The MAG 2-amide-RNA-conjugates were successfully Tc-99m-labeled with high yield and specific activities of 37MBq/nmol leading to 1:1-Tc-99m-N 3S-aptamers.