6- Chloro- pyridonepezils 4, 7 and 8 are potent hAChE inhibitors showing IC 50 in the 0.013–0.054 μM range. The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them ( 6) being a potent hBuChE inhibitor (IC 50 = 0.47 ± 0.08 μM). 6- Chloro- pyridonepezils 1– 8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile ( 13) with suitable 2-(1-benzylpiperidin-4-yl)alkylamines ( 9– 12). This review has four goals: (a) To survey and analyze critically the results of a flurry of research activity in this area in recent years, which has led to the preparation of a number of novel technetium-labeled radiopharmaceuticals targeted at high-affinity sites, a few of which appear to be very promising (b) to provide a conceptual analysis of how these agents are being designed (c) to provide a context in terms of binding and uptake behavior by which these agents should be judged and (d) to highlight emerging knowledge on the structure of receptors and related high-affinity binding biomolecules and their distribution, which may serve as reference points for understanding the results that have been obtained so far, and may be useful guides for future design.Ħ- Chloro- pyridonepezils are chloropyridine–donepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. Although many receptor-specific radiopharmaceuticals labeled with PET and other SPECT isotopes already exist, the low cost and widespread availability of technetium-99m would make their 99mTc-labeled counterparts much more accessible to the medical community. The development of technetium-99m-labeled small-molecule radiopharmaceuticals directed at specific high-affinity binding sites, as are found in receptors for hormones and neurotransmitters, transport systems, and certain enzymes, is a natural outgrowth from the successful development of technetium radiopharmaceuticals for imaging flow and metabolism. Although further structural studies are required, these findings implied that the Ham-based tetradentate ligands would serve as new chelating molecules for 99mTc radiopharmaceuticals. No decomposition with low protein binding were demonstrated when the two 99mTc complexes were incubated in murine plasma.

Selective complex formation of 99mTc with the two ligands was observed in the presence of human IgG. Reversed-phase HPLC analyses indicated that both C 2(BHam) 2 and C 3(BHam) 2 formed 99mTc complexes as single species with stabilities much higher than those of 99mTc-BHam. Complexation yields of over 95% were achieved at ligand concentrations as low as 2.5 × 10 −6 M. Both C 2(BHam) 2 and C 3(BHam) 2 formed 99mTc complexes with high yields over a wide pH range (pH 3–12) at room temperature. Synthetic procedures using oxadiazoline intermediates were developed for C 2(BHam) 2 and C 3(BHam) 2. Both N,N′-ethylene bis(benzohydroxamamide) and N,N′-propylene bis(benzohydroxamamide) were designed as new thiol-free chelating molecules for 99mTc radiopharmaceuticals.

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