Effective Labeling of Amine Pharmacophores through the Employment of 2,3-Pyrazinedicarboxylic Anhydride and the Generation of fac-[M(CO)₃(PyA)P] and cis–trans-[M(CO)₂(PyA)P₂] Complexes (PyA = Pyrazine-2-carboxylate, P = Phosphine, M = Re, ^99mTc)

The fac-[M­(CO)₃(PyA)­(P)] and cis–trans-[M­(CO)₂(PyA)­(P)₂] neutral complexes (M is Re or ^99mTc), based on the mixed ligand strategy with pyrazine-2-carboxylic acid (PyAH) as the bidentate N,O and triphenylphosphine as the monodentate P ligand, are presented. Through the employment of the anhydride of pyrazine-2,3-dicarboxylic acid (PyDA), the PyAH scaffold was conveniently derivatized with the model bioactive amine 1-(2-methoxyphenyl)­piperazine, the active part of the 5-HT_1A antagonist WAY100635. Reaction of either PyAH or the pharmacophore-bearing PyAH ligand (L¹H) with fac-[M­(CO)₃]⁺ core in water yielded the intermediate fac-[M­(CO)₃(PyA)­(H₂O)] complexes. The labile aqua ligand was easily replaced by PPh₃ to yield the fac-[Re­(CO)₃(PyA)­(PPh₃)] complexes, while in toluene under reflux, the cis–trans-[Re­(CO)₂(PyA)­(PPh₃)₂] complexes were obtained. The latter complexes were alternatively obtained from mer-[Re­(CO)₃(PPh₃)₂Cl] by refluxing with the PyA ligand in toluene. The analogous ^99mTc complexes were synthesized quantitatively, showing excellent stability in competition studies. The methodology described herein represents a practical procedure for the effective integration of the fac-[M­(CO)₃]⁺ core with amine-bearing biologically active compounds for diagnosis/therapy.