(99m) Tc Marker Of Dopamine D2 Receptor Imaging Agent

In vivo driagin teeboque of central nervus system (CNS) receptors with PET andSPECT provide a powerful tools for the diagnosis and the elucidation of pathologicalmechanisms in various neuropsychiatric disoders, and are expected to provid importantinformation in the evaluation of CNS function in normal or disease States and have asignifican boact in the drug develoPment process. Due to excellent nuclide properties andwide availability of^99mTc, development of^99mTc labeled CNS receptor imaging agents,Which may facilitate use of SPECT imaging of CNS receptor as a cost--effective clinicaltool, has been received considerable interest now.mimic sulPiride ligand, have been designed as a potential D2 receptor imaging agent.In this research, a reliable and reproducible Synthetic route of (S)-(-)-MBZM ligand[5-mercapto-N-((l-ethyl-2-pyrrolidinyl) methyl)-2 -methoxy benzamide] startin fromcommercially available 2-methoxy benzoic acid was devloped. Using the "3+1"mixedligand approach, a new neutral Re(v)O³⁺ complex, ReO(MBZM)(SNS), has beenconveniently synthesized by reacting MBZM and SNS [N-methyl-di(2-mercaptoethyl)amine] with ReOCl₃(PPh₃)₂ in alkaline methanol aqueous solution, and characterizedby IR, ¹H-NMR, fast atom bombardment MS and elemental analysis, respectively. Fromchemical view, two isomers can be expected When the amine substituent of SNS adopts asyn. or anti. configuration with respect to the M=O core. In this case, however, only oneisomer was obtained as well as in the case of n.c.a. preparation of^99mTc-MBZM.The desired ^99mTc radiolabeled compound was prepared throughligand-exchange reaction with ^99mTc(V)O³⁺ precursors, e.g ^99mTc-gluconate,oompc-GH After purified by a solid-phase extraction (SeP-pak Cl8 cartridge), theradio-chemical purity was more than 99% when tested by reversed-phase HPLC andTLC. The in vitro stability studies showed that 99m-MBZM remained stable atleast uP to 7h both in reaction matrix and resconstitued solution with phosphatebuffer (l00 mmol/l, pH 7.4) after isolated from excees ligands. When challengedwith cysteine (0.0l, 0.l and l.0 mmol/l) or glutothione (0.01, 0.l and l.0 mmolil)in phosphate buffer solution(l00 mmol/l, pH 7.4), it was, however, degradedraPidly.The binding affinity of ReO(MBZM)(SNS), which was emPloyed as surrogatefor oompc complex, was tested in a comPetition assay against ['H]-Spiperone. Afterintroduced metallic chelate moiety, the benzamide derivative displayed mediumaffinity for dopaxnine D2 receptor(Ki ==l23.5 nmoUl ).BiwhwhutiOn of tw-MBZM in male Haran Spragu Dawley rats has also beenundertak. mpMZM exhiited a fas blood clearane. Higher uPtake in the liver andlddncy MeSted tha radioaCtivity was excreted priIntw through hePatobilliny andurinny bo. Althugh ther was no sighfican drial brain UPtake (ouly 0.l45%ID/g, atM p.i.), the washout of radioaCtivity fiDm bdri was relatively slow (0.072%, eq, at15Inin P.i.: 0.072%, eq, at 30Inin P.i'). The uPtake and retention mechAnsm of99rnTnaZM in brain, Which may due to either itS exbo with GSH or bindin todoPamin reewt in the brain, remain to be tw investigated.