New ^99mTc(CO)₃‐radiolabeled arylpiperazine pharmacophore as potent 5HT_1A serotonin receptor radiotracer: Docking studies, chemical synthesis, radiolabeling, and biological evaluation

Abstract

In spite of previous efforts, there is lack of a radiotracer for imaging the 5HT 1A receptor density in human brain, which is involved in several neurological brain disorders. The aim of this study was to prepare a new derivative of 1-(2-methoxyphenyl)piperazine (MPP) as a main chemical structure of 5HT 1A receptor antagonist with 3-carbon linker and radiolabeled by [ 99m Tc][Tc(CO) 3 (H 2 O) 3 ] + precursor. Docking studies before chemical synthesis showed similar fashion of interaction for both WAY100635 (potent 5HT 1A receptor antagonist) and new designed ligand, despite of addition of 99m Tc(CO) 3 group in the structure of new ligand. MPP-(CH 2 ) 3 -N 3 was synthesized via three efficient and reliable chemical synthesis steps (more than 80% yield) then radiolabeled by addition of 2-ethynylpyridine and [ 99m Tc] [Tc(CO) 3 (H 2 O) 3 ] + precursor in one pot procedure (more than 95% radiochemical efficiency) through click chemistry method. After incubation, radiotracer was found stable in vitro up to 2 hours. Binding assays showed about 33% specific binding of radiotracer to the 5HT 1A receptors. Brain biodistribution studies indicated (0.26 ± 0.05)% ID/g hippocampus uptake at 30 minutes post injection, which its specificity was verified through blocking studies. These results suggested that new designed radioligand might serve as a potent SPECT imaging agent to estimate status of 5HT 1A receptors. KEYWORDS 1-(2-methoxyphenyl)piperazine (MPP), 2-ethynylpyridine, 5HT 1A homology model, click chemistry, docking, WAY100635

Click Chemistry and Radiochemistry: An Update

“…This approachdubbed “Click-to-Chelate” when it was first reported in 2006has most famously been used to create tridentate chelators for radiolabeling with Tc­(I) cores like [ 99m Tc]­[Tc­(CO) 3 (H 2 O) 3 ] + but has been employed with Re­(I) synthons as well. − Recently, Mindt and co-workers used this approach to synthesize 99m Tc-labeled probes in which the radiometal is sequestered by a tripodal N 2 O-based architecture created via the reaction of N α -propargyl lysine with an azide-bearing vector (Figure A). , Others have taken a similar approach to creating probes in which 99m Tc­(I) is coordinated by N 2 O- and NSO-containing coordination structures, most notably a multimodal, PSMA-targeted theranostic designed to facilitate both SPECT imaging and photodynamic therapy. ,− In yet another example, Erfani et al created a 99m Tc-labeled agent for the visualization of 5HT 1A serotonin receptors in the brain by clicking together 2-ethynylpyridine and an azide derived from 1-(2-methoxyphenyl)­piperazine (Figure B). The 99m Tc-labeled probe displayed brain uptake of 1.4 ± 0.1 %ID/g 15 min post-administration with hotspots in the 5HT 1A -active hippocampus . Finally, this approach has recently been extended beyond the realm of 99m Tc and its congeners by Wharton et al In this case, the investigators used the CuAAC reaction to create a bifunctional chelator, H 3 TPAN-triazole-Bn-NH 2 , in which the 1,2,3-triazole both coordinates the radiometal and attaches the chelator to the vector in question (Figure ).…”

“…The 99m Tclabeled probe displayed brain uptake of 1.4 ± 0.1 %ID/g 15 min post-administration with hotspots in the 5HT 1A -active hippocampus. 108 Finally, this approach has recently been extended beyond the realm of 99m Tc and its congeners by Wharton et al In this case, the investigators used the CuAAC reaction to create a bifunctional chelator, H 3 TPAN-triazole-Bn-NH 2 , in which the 1,2,3-triazole both coordinates the radiometal and attaches the chelator to the vector in question (Figure 9). 109 This acyclic chelator offers several advantages over extant options, including its synthetic accessibility, lack of steric hindrance, and compatibility with both 225 Ac and 111 In.…”