Dipicolinate Complexes of Gallium(III) and Lanthanum(III).

Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (H3dpaa), phosphonate (H4dppa), and bisphosphonate (H7dpbpa), as well as their nonfunctionalized analogue (H2dpa), were successfully synthesized and characterized. The 1:1 lanthanum(III) complexes of H2dpa, H3dpaa, and H4dppa, the 1:2 lanthanum(III) complex of H2dpa, and the 1:1 gallium(III) complex of H3dpaa were characterized, including via X-ray crystallography for [La4(dppa)4(H2O)2] and [Ga(dpaa)(H2O)]. H2dpa, H3dpaa, and H4dppa were evaluated for their thermodynamic stability with lanthanum(III) via potentiometric and either UV-vis spectrophotometric (H3dpaa) or NMR spectrometric (H2dpa and H4dppa) titrations, which showed that the carboxylate (H3dpaa) and phosphonate (H4dppa) containing ligands enhanced the lanthanum(III) complex stability by 3-4 orders of magnitude relative to the unfunctionalized ligand (comparing log ßML and pM values) at physiological pH. In addition, potentiometric titrations with H3dpaa and gallium(III) were performed, which gave significantly (8 orders of magnitude) higher thermodynamic stability constants than with lanthanum(III). This was predicted to be a consequence of better size matching between the dipicolinate cavity and gallium(III), which was also evident in the aforementioned crystal structures. Because of a potential link between lanthanum(III) and osteoporosis, the ligands were tested for their bone-directing properties via a hydroxyapatite (HAP) binding assay, which showed that either a phosphonate or bisphosphonate moiety was necessary in order to elicit a chemical binding interaction with HAP. The oral activity of the ligands and their metal complexes was also assessed by experimentally measuring log Po/w values using the shake-flask method, and these were compared to a currently prescribed osteoporosis drug (alendronate). Because of the potential therapeutic applications of the radionuclides 67/68Ga, radiolabeling studies were performed with 67Ga and H3dpaa. Quantitative radiolabeling was achieved at pH 6.5 in 10 min at room temperature with concentrations as low as 10-5 M, and human serum stability studies were undertaken.

Gallium(iii) and iron(iii) complexes of quinolone antimicrobials.

Iron is an essential nutrient for many microbes. According to the "Trojan Horse Hypothesis", biological systems have difficulties distinguishing between Fe(3+) and Ga(3+), which constitutes the antimicrobial efficacy of the gallium(iii) ion. Nine novel tris(quinolono)gallium(iii) complexes and their corresponding iron(iii) analogs have been synthesized and fully characterized. Quinolone antimicrobial agents from three drug generations were used in this study: ciprofloxacin, enoxacin, fleroxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, oxolinic acid, and pipemidic acid. The antimicrobial efficacy of the tris(quinolono)gallium(iii) complexes was studied against E. faecalis and S. aureus (both Gram-positive), as well as E. coli, K. pneumonia, and P. aeruginosa (all Gram-negative) in direct comparison to the tris(quinolono)iron(iii) complexes and the corresponding free quinolone ligands at various concentrations. For the tris(quinolono)gallium(iii) complexes, no combinational antimicrobial effects between Ga(3+) and the quinolone antimicrobial agents were observed.

Novel "bi-modal" H2dedpa derivatives for radio- and fluorescence imaging.

A novel pyridyl functionalized analog of the promising hexadentate 68Ga3+ chelate H2dedpa (N4O2, 1,2-[[6-carboxy-pyridin-2-yl]-methylamine]ethane) was successfully synthesized and characterized. This new bifunctional chelate (BFC) was used to prepare the first proof-of-principle bi-modal H2dedpa derivative for fluorescence and nuclear imaging. Two bi-modal H2dedpa derivatives were prepared: H2dedpa-propylpyr-FITC and H2dedpa-propylpyr-FITC-(N,N'-propyl-2-NI) (FITC=fluorescein, pyr=pyridyl functionalized, NI=nitroimidazole). The ligands possess the strong gallium-coordinating atoms contained within dedpa2- that are ideal for radiolabeling with 68Ga3+ for positron-emission tomography (PET) imaging, and two fluorophores for optical imaging. In addition, one analog contains two NI moieties for specific entrapment of the tracer in hypoxic cells. These new bi-modal analogs were compared to the native unfunctionalized H2dedpa scaffold to determine the extent to which the addition of pyridyl functionalization would affect metal coordination, and complex stability. The non-radioactive gallium complexes were tested in a 3D tumor spheroid model. The novel pyridyl bis-functionalized H2dedpa ligand, H2dedpa-propylpyr-NH2, was quantitatively radiolabeled with 67Ga (RCY>99%) under reaction conditions commensurate with unfunctionalized H2dedpa (10min at room temperature) at ligand concentrations as low as 10-5M. The resultant 67Ga-complex withstood transchelation to the in vivo metal-binding competitor apo-transferrin (2h at 37°C, 93% intact), signifying that [Ga(dedpa-propylpyr-NH2)]+ is a kinetically inert complex suitable for in vivo use, but exhibited slightly reduced stability compared to the native [67Ga(dedpa)] scaffold (>99% intact). Finally, bi-model fluorescent Ga-dedpa compounds were successfully imaged in a 3D tumor spheroid model. The Ga-dedpa-FITC-NI derivative was specifically localized in the central hypoxic core of the spheroid.

3-Hydroxy-4-pyridinone derivatives designed for fluorescence studies to determine interaction with amyloid protein as well as cell permeability.

Finding a cure for Alzheimer's disease is an urgent goal. Multifunctional metal binders are used to elucidate its pathological features and investigated as potential therapeutics. The use of physicochemical and TD-DFT calculations constituted successful strategy in the design of 1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL21) and 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL22). We report the synthesis and full characterization of these compounds, including X-ray crystallography. Using fluorescent signal as the readout, it was determined that HL22 interacts with amyloid-beta protein fibrils, and permeates into bEnd.3 cells used as a mimic of the blood-brain barrier. This provides the first example of direct investigation of our hydroxypyridinone compounds within a biological setting.

H2CHXdedpa and H4CHXoctapa-chiral acyclic chelating ligands for (67/68)Ga and (111)In radiopharmaceuticals.

The chiral acyclic ligands H2CHXdedpa (N4O2), H2CHXdedpa-bb (N4O2), and H4CHXoctapa (N4O4) (CHX = cyclohexyl/cyclohexane, H2dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane, bb = N,N'-dibenzylated, H4octapa = N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid) were synthesized, complexed with Ga(III) and/or In(III), and evaluated for their potential as chelating agents in radiopharmaceutical applications. The ligands were compared to the previously studied hexadentate H2dedpa and octadentate H4octapa ligands to determine the effect adding a chiral 1R,2R-trans-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga(CHXdedpa)](+) showed very similar properties to those of [Ga(dedpa)](+), with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga(dedpa)](+), [Ga(CHXdedpa)](+) exhibited exceptionally high thermodynamic stability constants (log KML = 28.11(8)), and the chelate retained the ability to label (67)Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10(-5) M. In vitro kinetic inertness assays demonstrated the [(67)Ga(CHXdedpa)](+) complex to be more stable than [(67)Ga(dedpa)](+) in a human serum competition, with 90.5% and 77.8% of (67)Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H4CHXoctapa with In(III) demonstrated [In(CHXoctapa)](-) to have an equivalently high thermodynamically stable constant as [In(octapa)](-), with log KML values of 27.16(9) and 26.76(14), respectively. The [(111)In(CHXoctapa)](-) complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [(111)In(octapa)](-) values, and an improved stability compared to the current industry "gold standards" 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA). Initial investigations reveal that the chiral acyclic hexadentate H2CHXdedpa and octadentate H4CHXoctapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively.

Ion exchange in hydroxyapatite with lanthanides.

Naturally occurring hydroxyapatite, Ca5(PO4)3(OH) (HAP), is the main inorganic component of bone matrix, with synthetic analogues finding applications in bioceramics and catalysis. An interesting and valuable property of both natural and synthetic HAP is the ability to undergo cationic and anionic substitution. The lanthanides are well-suited for substitution for the Ca(2+) sites within HAP, because of their similarities in ionic radii, donor atom requirements, and coordination geometries. We have used isothermal titration calorimetry (ITC) to investigate the thermodynamics of ion exchange in HAP with a representative series of lanthanide ions, La(3+), Sm(3+), Gd(3+), Ho(3+), Yb(3+) and Lu(3+), reporting the association constant (Ka), ion-exchange thermodynamic parameters (ΔH, ΔS, ΔG), and binding stoichiometry (n). We also probe the nature of the La(3+):HAP interaction by solid-state nuclear magnetic resonance ((31)P NMR), X-ray diffraction (XRD), and inductively coupled plasma-optical emission spectroscopy (ICP-OES), in support of the ITC results.

Iron(III)-binding of the anticancer agents doxorubicin and vosaroxin.

The Fe(iii)-binding constant of vosaroxin, an anticancer quinolone derivative, has been determined spectrophotometrically and compared with the analogous Fe(iii) complex formed with doxorubicin. The in vivo metabolic stability and iron coordination properties of the quinolones compared to the anthracylines may provide significant benefit to cardiovascular safety. The mechanism of action of both molecules target the topoisomerase II enzyme. Both doxorubicin (Hdox, log ßFeL3 = 33.41, pM = 17.0) and vosaroxin (Hvox, log ßFeL3 = 33.80(3), pM = 15.9) bind iron(iii) with comparable strength; at physiological pH however, [Fe(vox)3] is the predominant species in contrast to a mixture of species observed for the Fe:dox system. Iron(iii) nitrate and gallium(iii) nitrate at a 1 : 3 ratio with vosaroxin formed stable tris(vosaroxacino)-iron(iii) and tris(vosaroxino)gallium(iii) complexes that were isolated and characterized. Their redox behavior was studied by CV, and their stereochemistry was further explored in temperature dependent (1)H NMR studies. The molecular pharmacology of their interaction with iron(iii) may be one possible differentiation in the safety profile of quinolones compared to anthracyclines in relation to cardiotoxicity.

What a difference a carbon makes: H4octapa vs H4C3octapa, ligands for In-111 and Lu-177 radiochemistry.

The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal-ligand matching. It was found that [In(C3octapa)](-) and [Lu(C3octapa)](-) were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by (1)H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)](-) and [Lu(octapa)](-) revealed very symmetric complexes; in contrast, the [In(C3octapa)](-) and [Lu(C3octapa)](-) complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log K(ML), pM) were ~2 units lower for the In(3+) and Lu(3+) complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (~2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with (111)In and (177)Lu. Over a 5 day stability challenge experiment in blood serum, (111)In-octapa- and (111)In-C3octapa-trastuzumab immunoconjugates were determined to be ~91 and ~24% stable, respectively, and (177)Lu-octapa- and (177)Lu-C3octapa-trastuzumab, ~89% and ~4% stable, respectively. This work suggests that 5-membered chelate rings are superior to 6-membered chelate rings for large metal ions like In(3+) and Lu(3+), which is a crucial consideration for the design of bifunctional chelates for bioconjugation to targeting vectors for in vivo work.

Modular syntheses of H4octapa and H2dedpa, and yttrium coordination chemistry relevant to 86Y/9°Y radiopharmaceuticals.

The ligands H2dedpa, H4octapa, p-SCN-Bn-H2dedpa, and p-SCN-Bn-H4octapa were synthesized using a new protection chemistry approach, with labile tert-butyl esters replacing the previously used methyl esters as protecting groups for picolinic acid moieties. Additionally, the ligands H2dedpa and p-SCN-Bn-H2dedpa were synthesized using nosyl protection chemistry for the first time. The use of tert-butyl esters allows for deprotection at room temperature in trifluoroacetic acid (TFA), which compares favorably to the harsh conditions of refluxing HCl (6 M) or LiOH that were previously required for methyl ester cleavage. H4octapa has recently been shown to be a very promising (111)In and (177)Lu ligand for radiopharmaceutical applications; therefore, coordination chemistry studies with Y(3+) are described to assess its potential for use with (86)Y/(90)Y. The solution chemistry of H4octapa with Y(3+) is shown to be suitable via solution NMR studies of the [Y(octapa)](-) complex and density functional theory (DFT) calculations of the predicted structure, suggesting properties similar to those of the analogous In(3+) and Lu(3+) complexes. The molecular electrostatic potential (MEP) was mapped onto the molecular surface of the DFT-calculated coordination structures, suggesting very similar and even charge distributions between both the Lu(3+) and Y(3+) complexes of octapa(4-), and coordinate structures between 8 (ligand only) and 9 (ligand and one H2O). Potentiometric titrations determined H4octapa to have a formation constant (log K(ML)) with Y(3+) of 18.3 ± 0.1, revealing high thermodynamic stability. This preliminary work suggests that H4octapa may be a competent ligand for future (86)Y/(90)Y radiopharmaceutical applications.

3-Hydroxy-4-pyridinone derivatives as metal ion and amyloid binding agents.

Metal ions have been implicated in several neurodegenerative diseases, including Alzheimer's disease, as their dyshomeostasis may lead to production of reactive oxygen species as well as increased toxicity of amyloid protein aggregates. In this work, we present design and synthesis of three novel multifunctional hydroxypyridinone ligands, HL11, HL12, and HL13, bearing benzothiazole and benzoxazole functionalities. We study the ability of these compounds to bind metal ions Cu(II), Zn(II), and Fe(III), as well as their antioxidant activity and cytotoxicity. Additionally, we determine the pro-ligands' (compounds prior to chelation) propensity to target amyloid protein. Through these studies we determine the effect of combining amyloid- and metal-binding functionalities within the HPO scaffold on different aspects of AD pathology.

H(4)octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy.

A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCN-Bn-H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes (111)In and (177)Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94-95%) than those based on DOTA-trastuzumab (60 min, 37 °C, ~50-88%). Further, antibody integrity was better preserved in the (111)In- and (177)Lu-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93-0.95 for (111)In- and (177)Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for (111)In- and (177)Lu-octapa-trastuzumab compared to (111)In- and (177)Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios.

In vitro studies of lanthanide complexes for the treatment of osteoporosis.

Lanthanide ions, Ln(III), are of interest in the treatment of bone density disorders because they are found to accumulate preferentially in bone (in vivo), have a stimulatory effect on bone formation, and exhibit an inhibitory effect on bone degradation (in vitro), altering the homeostasis of the bone cycle. In an effort to develop an orally active lanthanide drug, a series of 3-hydroxy-4-pyridinone ligands were synthesized and eight of these ligands (H1 = 3-hydroxy-2-methyl-1-(2-hydroxyethyl)-4-pyridinone, H2 = 3-hydroxy-2-methyl-1-(3-hydroxypropyl)-4-pyridinone, H3 = 3-hydroxy-2-methyl-1-(4-hydroxybutyl)-4-pyridinone, H4 = 3-hydroxy-2-methyl-1-(2-hydroxypropyl)-4-pyridinone, H5 = 3-hydroxy-2-methyl-1-(1-hydroxy-3-methylbutan-2-yl)-4-pyridinone, H6 = 3-hydroxy-2-methyl-1-(1-hydroxybutan-2-yl)-4-pyridinone, H7 = 1-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone, H8 = 1-carboxyethyl-3-hydroxy-2-methyl-4-pyridinone) were coordinated to Ln(3+) (Ln = La, Eu, Gd, Lu) forming stable tris-ligand complexes (LnL(3), L = 1(-), 2(-), 3(-), 4(-), 5(-), 6(-), 7(-) and 8(-)). The dissociation (pK(an)) and metal ligand stability constants (log ß(n)) of the 3-hydroxy-4-pyridinones with La(3+) and Gd(3+) were determined by potentiometric titrations, which demonstrated that the 3-hydroxy-4-pyridinones form stable tris-ligand complexes with the lanthanide ions. One phosphinate-EDTA derivative (H(5)XT = bis[[bis(carboxymethyl)amino]methyl]phosphinate) was also synthesized and coordinated to Ln(3+) (Ln = La, Eu, Lu), forming the potassium salt of [Ln(XT)](2-). Cytotoxicity assays were carried out in MG-63 cells; all the ligands and metal complexes tested were observed to be non-toxic to this cell line. Studies to investigate the toxicity, cellular uptake and apparent permeability (P(app)) of the lanthanide ions were conducted in Caco-2 cells where it was observed that [La(XT)](2-) had the greatest cell uptake. Binding affinities of free lanthanide ions (Ln = La, Gd and Lu), metal complexes and free 3-hydroxy-4-pyridinones with the bone mineral hydroxyapatite (HAP) are high, as well as moderate to strong for the free ligand with the bone mineral depending on the functional group.

Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.

Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.

Evaluation of the H2)dedpa scaffold and its cRGDyK conjugates for labeling with 64Cu.

Studies of the acyclic ligand scaffold H(2)dedpa and its derivatives with the peptide cRGDyK for application in copper radiopharmaceuticals are described. Previously shown to be a superb ligand for (67/68)Ga, the chelate is now shown to coordinate (64)Cu in its derivatized and nonderivatized forms rapidly under mild reaction conditions (10 min, RT, pH 5.5 10 mM sodium acetate buffered solution). The hexadentate, distorted octahedral coordination of H(2)dedpa is confirmed in the corresponding solid state X-ray crystal structure of [Cu(dedpa)]. Cyclic voltammetry determined the reduction potential of [Cu(dedpa)] to be below values found for common bioreductants. Reduction and reoxidation were irreversible but reproducible, indicating a potential change of coordination mode upon reduction of Cu(II) to Cu(I). The thermodynamic stability constant log K(CuL) was determined to be 19.16(5), comparable to other frequently used (64)Cu chelates. Serum stability of the (64)Cu labeled chelate revealed only 3% transchelation/association to serum proteins after 2 h, while the conjugates reveal 10% ([Cu(RGD1)]) and 6% ([Cu(RGD2)]) transchelation at the same time point.

H4octapa: an acyclic chelator for 111In radiopharmaceuticals.

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.

Acyclic chelate with ideal properties for (68)Ga PET imaging agent elaboration.

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.