This preliminary investigation of the octadentate acyclic chelator H(4)octapa (N(4)O(4)) with (111)In/(115)In(3+) has demonstrated it to be an improvement on the shortcomings of the current industry "gold standards" DOTA (N(4)O(4)) and DTPA (N(3)O(5)). The ability of H(4)octapa to radiolabel quantitatively (111)InCl(3) at ambient temperature in 10 min with specific activities as high as 2.3 mCi/nmol (97.5% radiochemical yield) is presented. In vitro mouse serum stability assays have demonstrated the (111)In complex of H(4)octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [(111)In(octapa)](-) has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [(111)In(DOTA)](-), demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. (1)H/(13)C NMR studies of the [In(octapa)](-) complex revealed a 7-coordinate solution structure, which forms a single isomer and exhibits no observable fluxional behavior at ambient temperature, an improvement to the multiple isomers formed by [In(DTPA)](2-) and [In(DOTA)](-) under the same conditions. Potentiometric titrations have determined the thermodynamic formation constant of the [In(octapa)](-) complex to be log K(ML) = 26.8(1). Through the same set of analyses, the [(111/115)In(decapa)](2-) complex was found to have nonoptimal stability, with H(5)decapa (N(5)O(5)) being more suitable for larger metal ions due to its higher potential denticity (e.g., lanthanides and actinides). Our initial investigations have revealed the acyclic chelator H(4)octapa to be a valuable alternative to the macrocycle DOTA for use with (111)In, and a significant improvement to the acyclic chelator DTPA.

Nuclear medicine is composed of two complementary areas, imaging and therapy. Positron emission tomography (PET) and single-photon imaging, including single-photon emission computed tomography (SPECT), comprise the imaging component of nuclear medicine. These areas are distinct in that they exploit different nuclear decay processes and also different imaging technologies. In PET, images are created from the 511 keV photons produced when the positron emitted by a radionuclide encounters an electron and is annihilated. In contrast, in single-photon imaging, images are created from the γ rays (and occasionally X-rays) directly emitted by the nucleus. Therapeutic nuclear medicine uses particulate radiation such as Auger or conversion electrons or β − or α particles. All three of these technologies are linked by the requirement that the radionuclide must be attached to a suitable vector that can deliver it to its target. It is imperative that the radionuclide remain attached to the vector before it is delivered to its target as well as after it reaches its target or else the resulting image (or therapeutic outcome) will not reflect the biological process of interest. Radiochemistry is at the core of this process, and radiometals offer radiopharmaceutical chemists a tremendous range of options with which to accomplish these goals. They also offer a wide range of options in terms of radionuclide half-lives and emission properties, providing the ability to carefully match the decay properties with the desired outcome. This Review provides an overview of some of the ways this can be accomplished as well as several historical examples of some of the limitations of earlier metalloradiopharmaceuticals and the ways that new technologies, primarily related to radionuclide production, have provided solutions to these problems.

We have investigated novel bifunctional chelate alternatives to the aminocarboxylate macrocycles NOTA (N(3)O(3)) or DOTA (N(4)O(4)) for application of radioisotopes of Ga to diagnostic nuclear medicine and have found that the linear N(4)O(2) chelate H(2)dedpa coordinates (67)Ga quantitatively to form [(67)Ga(dedpa)](+) after 10 min at RT. Concentration-dependent coordination to H(2)dedpa of either (68)Ga or (67)Ga showed quantitative conversion to the desired products with ligand concentrations as low as 10(-7) M. With (68)Ga, specific activities as high as 9.8 mCi nmol(-1) were obtained without purification. In a 2 h competition experiment against human apo-transferrin, [(67)Ga(dedpa)](+) showed no decomposition. Two bifunctional versions of H(2)dedpa are also described, and these both coordinate to (67)Ga at RT within 10 min. Complete syntheses, characterizations, labeling studies, and biodistribution profiles of the (67)Ga complexes are presented for the new platform chelates. The stability of these platform chelates is higher than that of DOTA.

Metal-based drugs and imaging agents are extensively used in the clinic for the treatment and diagnosis of cancers and a wide range of other diseases. The current clinical arsenal of compounds operate via a limited number of mechanisms, whereas new putative compounds explore alternative mechanisms of action, which could potentially bring new chemotherapeutic approaches into the clinic. In this review, metal-based drugs and imaging agents are characterized according to their primary mode of action and the key properties and features of each class of compounds are defined, wherever possible. A better understanding of the roles played by metal compounds at a mechanistic level will help to deliver new metal-based therapies to the clinic, by providing an alternative, targeted and rational approach, to supplement non-targeted screening of novel chemical entities for biological activity. The Bigger Picture The use of metal complexes in medicine to diagnose or treat patients with different medical conditions is well-established. However, the field is currently undergoing a paradigm shift; formerly, following the discovery of a useful compound, the primary mechanism of action was subsequently investigated, whereas today, the mechanism of action is increasingly used to drive the discovery process. This approach benefits from the specific properties of metal complexes that can be tuned to optimize the drug-like properties of the metal compound. In this review, we provide an analysis of the primary modes of action of the currently used metal-based drugs and promising drug candidates, and highlight both the challenges and opportunities offered by these compounds.