Search

A detailed study was conducted to obtain a novel bifunctional chelate alternatives to the aminocarboxylate macrocycles NOTA ([N.sub.3][O.sub.3]) or DOTA [N.sub.4][O.sub.4]) for application of radioisotopes of Ga to diagnostic nuclear medicine. The results from the complete syntheses, characterizations, labeling studies, and biodistribution profiles of the linear [N.sub.4][O.sub.2] chelate [H.sub.2]dedpa which coordinates [super 67]Ga quantitatively to form [[super 67]Ga(dedpa)](+) after 10 min at RT represents the new platform chelates with higher stability than that of DOTA.

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 67Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10-5 M. In vitro kinetic inertness assays demonstrated the [67Ga(CHXdedpa)]+ complex to be more stable than [67Ga(dedpa)]+ in a human serum competition, with 90.5% and 77.8% of 67Ga 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 [111In(CHXoctapa)]- complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [111In(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. [ABSTRACT FROM AUTHOR]

The ligands H2dedpa, H2octapa, p-SCN-Bn-H4dedpa, 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 111In and 177Lu ligand for radiopharmaceutical applications; therefore, coordination chemistry studies with Y3+ are described to assess its potential for use with 86Y/90Y. The solution chemistry of H4octapa with Y3+ 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 In3+ and Lu3+ 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 Lu3+ and Y3+ complexes of octapa4-, and coordinate structures between 8 (ligand only) and 9 (ligand and one H2O). Potentiometric titrations determined H4octapa to have a formation constant (log KML) with Y3+ of 18.3 ± 0.1, revealing high thermodynamic stability. This preliminary work suggests that H4octapa may be a competent ligand for future 86Y/90Y radiopharmaceutical applications. [ABSTRACT FROM AUTHOR]

Studies of the acyclic ligand scaffold H2dedpa and its derivatives with the peptide cRGDyK for application in copper radiopharmaceuticals are described. Previously shown to be a superb ligand for 67/68Ga, die chelate is now shown to coordinate 64Cu 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 H2dedpa is confirmed in the corresponding solid state X-ray crystal structure of [Cu(dedpa)]. Cyclic voltarnmetry 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 KCuL was determined to be 19.16(5), comparable to other frequently used 64Cu chelates. Serum stability of the 64Cu labeled chelate revealed only 3% transchelation/association to serum proteins after 2 h, while the conjugates reveal 10% ([Cu(RGDl)]) and 6% ([Cu(RGD2)]) transchelation at the same time point. [ABSTRACT FROM AUTHOR]

This preliminary investigation of the octadentate acyclic chelator H4octapa (N4O4) with 111In/115In3+ has demonstrated it to be an improvement on the shortcomings of the current industry "gold standards" DOTA (N4O4) and DTPA (N3O5). The ability of H4octapa to radiolabel quantitatively 111InCl3 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 111In complex of H4octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [111In(octapa)]- has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [111In(DOTA)]-, demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. 1H/13C 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 KML = 26.8(1). Through the same set of analyses, the [111/115In(decapa)]2- complex was found to have nonoptimal stability, with H5decapa (N5O5) 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 H4octapa to be a valuable alternative to the macrocycle DOTA for use with 111In, and a significant improvement to the acyclic chelator DTPA. [ABSTRACT FROM AUTHOR]

We have investigated novel bifunctional chelate alternatives to the arninocarboxylate macrocycles NOTA (N3O3) or DOTA (N4O4) for application of radloisotopes of Ga to diagnostic nuclear medicine and have found that the linear N4O2 chelate H2dedpa coordinates 67Ga quantitatively to form [67Ga(dedpa)]+ after 10 min at RT. Concentration-dependent coordination to H2dedpa of either 68Ga or 67Ga showed quantitative conversion to the desired products with ligand concentrations as low as 10-7 M. With 68Ga, specific activities as high as 9.8 mCi nmol-1 were obtained without purification. In a 2 h competition experiment against human apo-transferrin, [67Ga(dedpa)]+ showed no decomposition. Two bifunctional versions of H2dedpa are also described, and these both coordinate to 67Ga at RT within 10 min. Complete syntheses, characterizations, labeling studies, and biodistribution profiles of the 67Ga complexes are presented for the new platform chelates. The stability of these platform chelates is higher than that of DOTA. [ABSTRACT FROM AUTHOR]

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.