SYNTHESIS AND RECEPTOR-BINDING PROPERTIES OF FLUORO-SUBSTITUTED AND IODO-SUBSTITUTED HIGH-AFFINITY SIGMA-RECEPTOR LIGANDS - IDENTIFICATION OF POTENTIAL PET AND SPECT SIGMA-RECEPTOR IMAGING AGENTS

Unlabeled fluoro- and iodo-substituted ligands exhibiting very high affinity and selectivity for sigma-receptors were synthesized based on three different structural classes of sigma-receptor ligands. These compounds were evaluated for sigma-receptor affinity and specificity in order to assess their potential as PET/SPECT imaging agents. Thus, (+)- and (-)-N-(5-fluoro-1-pentyl)normetazocines [(+)- and (-)-41 based on the (+)-benzomorphan class of sigma-ligands were synthesized via N-alkylation of optically pure (+)- and (-)-normetazocine with 5-[(methylsulfonyl)oxyl-l-pentyl fluoride (11). (+)- and (-)-4 displaced [H-3](+)-3-PPP with K(i) values of 0.29 and 73.6 nM and [H-3](+)-pentazocine with K(i) values of 10.5 and 38.9 nM, respectively. The second class of PET/SPECT ligands was based upon the N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine class of sigma-ligands; N-[2-(3,4-dichlorophenyl)-l-ethyl]-N-(3-fluoro-1-propyl)-2-(1-pyrrolidinyl)ethylamine (5) was obtained via N-alkylation of N-[2-(3,4-dichlorophenyl)-l-ethyl]-2-(1-pyrrolidinyl)ethylamine (14) with 3-fluoropropyl p-toluenesulfonate. 5 exhibited K(i) values of 4.22 and 5.07 nM for displacement of [H-3] (+)-3-PPP and [H-3] (+)-pentazocine, respectively, comparable with the parent N-propyl compound. Attempts to synthesize N-[2-(3,4-dichlorophenyl)-1-ethyl]-N-[3-[(methylsulfonyl)oxy]-1-propyl]-2-(1-pyrrolidinyl)ethylamine (26), a precursor to 5 that could conceivably be converted to [F-18]-5 by treatment with F-18, proved unsuccessful. The sequence of regioselective nitration, catalytic hydrogenation, and diazotization followed by NaI quench of N-[2-(3,dichlorophenyl)-1-ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (2) afforded the iodinated ethylenediamine N-[2-(2-iodo-4,5-dichlorophenyl)-1-ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (8), a potential SPECT ligand for sigma-receptors. This compound showed an affinity of 0.54 nM ([H-3](+)-3-PPP) comparable with the parent compound 2 (K(i) = 0.34 nM, [H-3](+)-3-PPP). Ligand 8 exhibited a similar potency against [H-3](+)-pentazocine. The third class of high-affinity sigma-receptor ligands was rationalized based on rearrangement of the bonds in ethylenediamine 2 to give 1-[2-(3,4-dichlorophenyl)-l-ethyl]-4-(1-propyl)piperazine (3). This compound exhibited very high affinity (K(i) = 0.31 nM, [H-3](+)-3-PPP) and selectivity for sigma-receptors. Compound 3 was synthesized in three steps from commercially available 1-propylpiperazine and served as a template for the synthesis of PET and SPECT compounds 1-[3-fluoro-(1-propyl)]4[2-(3,4-dichlorophenyl)ethyl]piperazine (6) (K(i) = 4.24 nM, [H-3](+)-3-PPP), 1-(5-fluoro-1-pentyl)-4-[2-(3,4-dichlorophenyl)ethyl]piperazine (7) (K(i) = 0.86 nM, [H-3](+)-3-PPP), and 1-(3-iodo-1-propyl)-4- [2-(3,4-dichlorophenyl)ethyl]piperazine (9) (K(i) = 1.32 nM, [H-3] (+)-3-PPP). Compound 7 was synthesized via N-alkylation of 1-(3,4-dichlorophenylacetyl)piperazine (19) with 11, followed by AlH3 reduction. Ligands 6 and 9 were obtained via reaction between 1-[3-[(methylsulfonyl)oxy]-1-propyl]-4-[2-(3,4-dichlorophenyl)ethyl]piperazine (22) and the corresponding anions F- (in acetonitrile) and I- (in acetone). The ease of generation of 6 and 9 from methanesulfonate ester 22 and of 8 from the corresponding aniline 29 combined with their very high affinity identifies them as potentially useful PET/SPECT ligands. All compounds 4-9 displayed very high a receptor affinity and showed low to negligible affinity for several receptor systems which commonly cross-react with sigma-ligands (kappa, phencyclidine, D2-dopamine, and muscarinic/cholinergic). In general, it appeared that the K(i) values for displacement of [H-3](+)-3-PPP correlated with those obtained for displacement of [H-3](+)-pentazocine, suggesting that these compounds interact with the same population of sigma-receptors. However, exceptions observed with (+)-4 and 6 suggest a more complex interaction with a sites.