In vivo evaluation of radioiodinated 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)-piperazine derivatives as new ligands for sigma receptor imaging using single photon emission computed tomography.

New series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-[3-(2-iodophenyl)propyl]piperazine (o-BON) and 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-[3-(3-iodophenyl)propyl]piperazine (m-BON) were evaluated as single photon emission computed tomography (SPECT) radiopharmaceuticals for mapping sigma receptors in the central nervous system (CNS) and peripheral organs. In vivo biodistribution studies of [125I] o- and m-BON in mice demonstrated high initial uptakes and prolonged retention in the brain. In contrast to high brain uptake and retention, the blood accumulations were low, resulting in good brain-blood ratios (7.9-9.2). In the other tissues, high uptake of [125I] o- and m-BON were observed in the liver, kidney, heart, lung, and pancreas. Moreover, selective interactions of [125I] o- and m-BON with sigma receptors were confirmed by pretreatment experiments with various sigma and other receptor ligands. Haloperidol posttreatment induced decreases in the accumulation of [125I] o- and m-BON. These data suggest that [125I] o- and m-BON binding to sigma receptors is reversible and competitive. Furthermore, ex vivo autoradiograms of [125I] o- and m-BON in rats showed high uptake in the parietal cortex, vestibular nucleus, and pons nucleus and moderate uptake in the thalamus, inferior colliculus, hippocampus, hypothalamus, and temporal cortex. These ex vivo autoradiograms were comparable with the histochemical distribution of sigma receptors. Furthermore, the uptake of [125I] o- and m-BON reflected quantitative amounts of sigma receptor in the brain. These results demonstrated that radiolabeled o- and m-BON have good characteristics for mapping sigma receptors in the CNS and the peripheral organs with SPECT.

Synthesis and in vitro evaluation of iodinated derivatives of piperazine as a new ligand for sigma receptor imaging by single photon emission computed tomography.

A new series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) was synthesized and evaluated as a potential brain sigma-1 receptor imaging ligands by single photon emission computed tomography (SPECT). Iodinated analogues of SA4503 (4a-c) were prepared from piperazine in a high yield. The in vitro competition binding studies using [3H] DTG (sigma-1, 2), [3H] (+)-pentazocine (sigma-1), and [3H] DTG in the presence of carbetapentane (sigma-2) as sigma receptor selective radioligands were revealed that iodinated analogues 4a-c possess high affinities to sigma receptors (IC50: 4a=7.1, 4b=31.0, and 4c=77.3 nM). In particular, the affinity of 4a, bearing iodine at ortho position on the phenyl ring, was 4.4 times greater than SA4503, and 3 times greater than that of haloperidol. The meta-iodo analogue 4b was the same to SA4503, the lead compound. The radioiodinated derivatives, [125I] 4a, 4b were synthesized no-carrier-added from the corresponding tributyltin precursors by the iododestannylation reaction with high yields. The binding of [125I] 4a, 4b have been characterized in the rat brain membranes. These compounds were indicated single population binding to sigma receptor with high affinity (4a: Kd=1.86+/-0.34 nM, Bmax=205+/-28.9 fmol/mg protein, 4b: Kd=3.30+/-0.51 nM, Bmax=231.5+/-13.8 fmol/mg protein). In vitro blocking studies were confirmed that the high specificity of 4a, 4b. These results suggest that radioiodinated 4a and 4b are promising sigma receptors imaging ligand for pursuing further in vivo studies.