[6-chloro-3-pyridylmethyl-3H] neonicotinoids as high-affinity radioligands for the nicotinic acetylcholine receptor: Preparation using NaB3H4 and LiB3H4

Abstract

NaB3H4 and LiB3H4 at 78% and 97% isotopic enrichments, respectively, were used in the synthesis of 3H‐labeled 1‐(6‐chloro‐3‐pyridyl)‐methyl‐2‐nitromethyleneimidazolidine (CH‐IMI) and N′‐[(6‐chloro‐3‐pyridyl)methyl]‐N″‐cyano‐N′‐methylacetamidine (acetamiprid) (two very potent insecticides) and of 1‐(6‐chloro‐3‐pyridyl)methyl‐2‐iminoimidazolidine (desnitro‐IMI) (a metabolite of the commercial insecticide imidacloprid). 6‐Chloronicotinoyl chloride was treated with either NaB3H4 in methanol or LiB3H4 in tetrahydrofuran and the resulting alcohol transformed to 2‐chloro‐5‐chloromethylpyridine, which was then coupled to N‐cyano‐N′‐methylacetamidine to give [3H]acetamiprid (45 Ci/mmol). 2‐Chloro‐5‐chloro[3H]methylpyridine was also reacted with ethylenediamine and the product was either refluxed in absolute ethanol with 1,1‐bis(methylthio)‐2‐nitro‐ethylene to provide [3H]CH‐IMI or reacted in toluene with a solution of cyanogen bromide to produce [3H]desnitro‐IMI (each 55 Ci/mmol).

Radiosynthesis of tritium‐labeled novel nitromethylene neonicotinoids compounds with NaB3H4

“…The radiosynthesis of tritium‐labeled 2‐chloro‐5‐((2‐(nitromethylene) imidazolidin‐1‐yl)methyl)pyridine (6‐Cl‐PMNI) (Figure 1) has been reported by Latli et al ,9 which involves high specific activity NaB 3 H 4 and a multi‐step microsynthesis. It required microreactor and difficult operation to achieve the final resolution.…”

“…In this paper, a high‐specific radioactivity methanolic NaB 3 H 4 solution was first diluting by non‐labeled NaBH 4 , and this was taken to synthesize the target compounds offering the characteristics of a simple operation, high utilization ratio and providing sufficient quantities for further study. Various starting materials have been reported in introducing the tritium atoms into the flexible linkage 9–11. The reduction of 1 by sodium borohydride in anhydrous methanol achieved higher radiochemical yield.…”

Radiosynthesis of tritium‐labeled novel nitromethylene neonicotinoids compounds with NaB3H4

“…The radiosynthesis of tritium‐labeled 2‐chloro‐5‐((2‐(nitromethylene) imidazolidin‐1‐yl)methyl)pyridine (6‐Cl‐PMNI) (Figure 1) has been reported by Latli et al ,9 which involves high specific activity NaB 3 H 4 and a multi‐step microsynthesis. It required microreactor and difficult operation to achieve the final resolution.…”

“…In this paper, a high‐specific radioactivity methanolic NaB 3 H 4 solution was first diluting by non‐labeled NaBH 4 , and this was taken to synthesize the target compounds offering the characteristics of a simple operation, high utilization ratio and providing sufficient quantities for further study. Various starting materials have been reported in introducing the tritium atoms into the flexible linkage 9–11. The reduction of 1 by sodium borohydride in anhydrous methanol achieved higher radiochemical yield.…”

Novel and Potent 6-Chloro-3-pyridinyl Ligands for the α4β2 Neuronal Nicotinic Acetylcholine Receptor

“…17 Modifications of Heterocyclic Amine and Trialkylammonium Moieties of 6-Chloro-3-pyridinylScheme 1. Synthesis of 6-Chloro-3-pyridinylmethyl Ligands with Modifications in the Heterocyclic Imine Moiety (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) or Related Compounds (11)(12)(13)(14) methyl Ligands 18-23 (Scheme 2). The azetidine derivative 18 was prepared by coupling CCMP to 3-chloropropylamine in the usual manner, followed by cyclization in refluxing acetonitrile.…”

“…Prepared as before. 14 1-[(6-Chloro-3-pyridinyl)methyl]-1,3-diaminopropane. CCMP (1.62 g, 10 mmol) in acetonitrile (15 mL) was added dropwise to a solution of 1,3-diaminopropane (0.835 mL, 10 mmol) in acetonitrile (20 mL) over a period of 2 h at 25 °C.…”

Nitroso-Imidacloprid Irreversibly Inhibits Rabbit Aldehyde Oxidase

“…IMI-NO and IMI-NH 2 were obtained by the reduction of IMI as previously described (11). [ 3 H]IMI-NO was prepared from [ 3 H]IMI (12) by reduction with Raney Ni in ethanol (13) and was purified via preparative TLC on silica gel. More specifically, Raney Ni (80 mg) as a 50% slurry in water was washed twice with anhydrous ethanol (300 µL) and then transferred with anhydrous ethanol (2.6 mL) to a vial containing [ 3 H]IMI (20.8 mg, 0.08 mmol; 20 µCi/mmol).…”

Radiosynthesis of tritium‐labeled novel nitromethylene neonicotinoids compounds with NaB3H4

“…The radiosynthesis of tritium‐labeled 2‐chloro‐5‐((2‐(nitromethylene) imidazolidin‐1‐yl)methyl)pyridine (6‐Cl‐PMNI) (Figure 1) has been reported by Latli et al ,9 which involves high specific activity NaB 3 H 4 and a multi‐step microsynthesis. It required microreactor and difficult operation to achieve the final resolution.…”

“…In this paper, a high‐specific radioactivity methanolic NaB 3 H 4 solution was first diluting by non‐labeled NaBH 4 , and this was taken to synthesize the target compounds offering the characteristics of a simple operation, high utilization ratio and providing sufficient quantities for further study. Various starting materials have been reported in introducing the tritium atoms into the flexible linkage 9–11. The reduction of 1 by sodium borohydride in anhydrous methanol achieved higher radiochemical yield.…”

Novel and Potent 6-Chloro-3-pyridinyl Ligands for the α4β2 Neuronal Nicotinic Acetylcholine Receptor

“…17 Modifications of Heterocyclic Amine and Trialkylammonium Moieties of 6-Chloro-3-pyridinylScheme 1. Synthesis of 6-Chloro-3-pyridinylmethyl Ligands with Modifications in the Heterocyclic Imine Moiety (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) or Related Compounds (11)(12)(13)(14) methyl Ligands 18-23 (Scheme 2). The azetidine derivative 18 was prepared by coupling CCMP to 3-chloropropylamine in the usual manner, followed by cyclization in refluxing acetonitrile.…”

“…Prepared as before. 14 1-[(6-Chloro-3-pyridinyl)methyl]-1,3-diaminopropane. CCMP (1.62 g, 10 mmol) in acetonitrile (15 mL) was added dropwise to a solution of 1,3-diaminopropane (0.835 mL, 10 mmol) in acetonitrile (20 mL) over a period of 2 h at 25 °C.…”

Nitroso-Imidacloprid Irreversibly Inhibits Rabbit Aldehyde Oxidase

“…IMI-NO and IMI-NH 2 were obtained by the reduction of IMI as previously described (11). [ 3 H]IMI-NO was prepared from [ 3 H]IMI (12) by reduction with Raney Ni in ethanol (13) and was purified via preparative TLC on silica gel. More specifically, Raney Ni (80 mg) as a 50% slurry in water was washed twice with anhydrous ethanol (300 µL) and then transferred with anhydrous ethanol (2.6 mL) to a vial containing [ 3 H]IMI (20.8 mg, 0.08 mmol; 20 µCi/mmol).…”

Radiosynthesis of tritium‐labeled novel nitromethylene neonicotinoids compounds with NaB3H4

“…The radiosynthesis of tritium‐labeled 2‐chloro‐5‐((2‐(nitromethylene) imidazolidin‐1‐yl)methyl)pyridine (6‐Cl‐PMNI) (Figure 1) has been reported by Latli et al ,9 which involves high specific activity NaB 3 H 4 and a multi‐step microsynthesis. It required microreactor and difficult operation to achieve the final resolution.…”

“…In this paper, a high‐specific radioactivity methanolic NaB 3 H 4 solution was first diluting by non‐labeled NaBH 4 , and this was taken to synthesize the target compounds offering the characteristics of a simple operation, high utilization ratio and providing sufficient quantities for further study. Various starting materials have been reported in introducing the tritium atoms into the flexible linkage 9–11. The reduction of 1 by sodium borohydride in anhydrous methanol achieved higher radiochemical yield.…”

Novel and Potent 6-Chloro-3-pyridinyl Ligands for the α4β2 Neuronal Nicotinic Acetylcholine Receptor

“…17 Modifications of Heterocyclic Amine and Trialkylammonium Moieties of 6-Chloro-3-pyridinylScheme 1. Synthesis of 6-Chloro-3-pyridinylmethyl Ligands with Modifications in the Heterocyclic Imine Moiety (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) or Related Compounds (11)(12)(13)(14) methyl Ligands 18-23 (Scheme 2). The azetidine derivative 18 was prepared by coupling CCMP to 3-chloropropylamine in the usual manner, followed by cyclization in refluxing acetonitrile.…”

“…Prepared as before. 14 1-[(6-Chloro-3-pyridinyl)methyl]-1,3-diaminopropane. CCMP (1.62 g, 10 mmol) in acetonitrile (15 mL) was added dropwise to a solution of 1,3-diaminopropane (0.835 mL, 10 mmol) in acetonitrile (20 mL) over a period of 2 h at 25 °C.…”

Nitroso-Imidacloprid Irreversibly Inhibits Rabbit Aldehyde Oxidase

“…IMI-NO and IMI-NH 2 were obtained by the reduction of IMI as previously described (11). [ 3 H]IMI-NO was prepared from [ 3 H]IMI (12) by reduction with Raney Ni in ethanol (13) and was purified via preparative TLC on silica gel. More specifically, Raney Ni (80 mg) as a 50% slurry in water was washed twice with anhydrous ethanol (300 µL) and then transferred with anhydrous ethanol (2.6 mL) to a vial containing [ 3 H]IMI (20.8 mg, 0.08 mmol; 20 µCi/mmol).…”