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A. Kafsifis ct al.

relaxation, tolerancc and dependence and is comparablc Jo the characteristics of the partia! agonisls Brela/enil.¹'* Chronić udminisiration of this compound in pharmacological ly active duses in mice failed to induce tolerancc lo the effects of this drug on GABA_a receptor function.¹ Although the detailed moleeular intcractions of partia! allosteric modulators such as Imidazenil and Bretazenil have not been established, it has bccn suggcsled that che se)ectivc pharmacological efficacy may be atlribuied to preferential affinily or specific activation of subpopulations of GABAa rcccptors in distinct brain region*.⁴'⁷

-NUR

1	R = H.	X =* Br
2	R = H.	X = I
3	R = Elhyl,	X = Br
4	R= Elhyl.	X= l
5	R = H,	X = ^mI
6	R= Ethyl,	X= ^mI
18	R = H,	X = Sn(CH,),

Figurę I

The identification of structurally different and neuron specific GABA_a receptor subtypes suggests that a se!ective pharmacological profile could be obtaincd by the availabtlity of ligands with selectivc affinily for receptor subtypes." As a conseąuence there has been a substantial cffoit into the design and synthesis of ligands with distinct Chemical profiles and phannacologicai efficacy^yiu Likewise there has been a considerable effort towards the synthesis of radioligands for the in vitro and in vivo study of GABA_a rcceptors in neurodegencrative diseases using PET and SPECT.” ¹³ The presence of the brominc atom in the 2' position of imidazenil lends iLself to the development of other halogenatcd denvaiives with retention of biological and pharmacological activity. Initial scrccning of the iodinated analogues 2 and 4 indicated potent in vitro binding to the central benzodiazepine receptor (BZR) of 1.1 nM and 0.006 nM rcspectively, whilc the intermediate esters U and 16 revealed only a modernie affinity of 7.4 nM and 178 nM ([³H]flunitrazepam) iespectively (unpubhshed data). Based on these results and the need lo devclop suitable radiolracers for probing BZR’s using SPECT, wc chose to label compounds 2 and 4 with iodine-123. Herein we report the synthesis and radiolabeiling oi the partial agomsts imidazenil and N-ethyl imidazenil with iodine-123.

Results and Discussion

Imidazenil 1. N-cthylimidazenil 3 and the iodinated derivatives 2 and 4 were synthesiscd according to modified methods described in the literaturę’⁴'¹⁶ (Scheme 1). The 2-amino-5-fluorophenyl-(2'-bromophenyljmcthanone 8 and 2-amino-5-fluorophenyi-(2’-iodo{)henyl)methanone 13 were prepared by the condcnsation of the respective 2-halobcn2oyl chlorides with 4-fluoroaniIine in the picscnce of