A convenient synthetic procedure yielding 2-picolinamino-N,Ndiaceticacid monoamide derivatives, for labelling with the fac-M(CO)3+ core

摘要

In this study, an one step synthetic procedure was developed allowing the formation ofrntridentate ligands that are monoamido derivatives of picollimamino-N,N-diacetic acid (PADA)rnmolecule which binds efficiently with Re/Tc tricarbonyl core. This method simplifies to some extentrnthe incorporation of a biological active molecule which contains an amine group to the NNO donorrnatom system of PADA ligand providing thus an easy way for labelling a pharmacophore moiety withrntechnetium or rhenium. The synthetic scheme includes the preparation of the anhydride of PADA, 2.rnIts subsequent reaction with pyrolidine, aniline or 2-methoxyphenylpiperazine (a fragment of the truern5-HT1A antagonist WAY-100635) lead to the formation of corresponding NNO tridentate ligands, o-rn(C5H4N)CH2N(CH2COOH)CH2CON(CH2CH2)2 3a, o-(C5H4N)CH2N(CH2COOH)CH2CONHC6H5),rn3b, or o-(C5H4N)CH2N(CH2COOH)CH2CON(CH2CH2)2N(o-CH3OC6H4), 3c. All ligands were reactedrnsuccessfully with the fac-M(CO)3 cores (M = Re/99mTc). The rhenium complexes, Re(CO)3(NNO), 4acrnwere prepared by ligand exchange reactions using [Et4N][Re(CO)3Br3] as precursor. All complexesrnwere characterized by elemental analysis and spectroscopic methods. Complex 4a was furtherrncharacterized by X-ray crystallography. The in vitro affinity for the 5-HT1A receptors of the rheniumrncomplex 4c is in the nanomolar range (IC50 = 2 ± 0.3 nM). The analogues Tc-99m complexes,rn99mTc(CO)3(NNO) 5a-c, were prepared by ligand exchange reactions using [99mTc(CO)3(H2O)3]+ asrnprecursor. The identity of the 99mTc complexes was established by comparative HPLC analysis usingrnthe well characterized rhenium 4a-c complexes as reference. For biodistribution studies, the 5a and 5crncomplexes were administered in Swiss Albino mice. None of the new tracer agents showed significantrnbrain uptake. Both complexes exhibits rapid blood clearance and elimination mainly through thernhepatobiliary system.