The chiral acyclic ligands H(2)CHXdedpa (N4O2), H(2)CHXdedpa-bb (N4O2), and H(4)CHXoctapa (N4O4) (CHX = cyclohexyl/cyclohexane, H(2)dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane, bb = N,N'-dibenzylated, H(4)octapa = 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 H(2)dedpa and octadentate H(4)octapa 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 K= 28.11(8)), and the chelate retained the ability to labelGa quantitatively in 10 min at room temperature at ligand concentrations of 1 x 10(-5) M. In vitro kinetic inertness assays demonstrated the [Ga-67(CHXdedpa)](+) complex to be more stable than [Ga-67(dedpa)](+) in a human serum competition, with 90.5% and 77.8% of Ga-67 remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H(4)CHXoctapa with In(III) demonstrated [In(CHXoctapa)]- to have an equivalently high thermodynamically stable constant as [In(octapa)]-, with log K values of 27.16(9) and 26.76(14), respectively. The [In(CHXoctapa)]- complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [In-111(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 H(2)CHXdedpa and octadentate H(4)CHXoctapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively.