Chunyi Liu

(+)-9-Benzyloxy-α-dihydrotetrabenazine as an important intermediate for the VMAT2 imaging agents: absolute configuration and chiral recognition

This article reports, for the first time, on the absolute configuration of (+)-9-benzyloxy-α-dihydrotetrabenazine (8), as determined from the perspective of X-ray crystallography. Compound 8 was prepared by a six-step reaction using 3-benzyloxy-4-methoxybenzaldehyde (1) as a starting material. The X-ray crystal diffraction structure of two compounds, racemic 9-benzyloxy-tetrabenazine (5) and the diastereomeric salt of compound 8, is also described for the first time in this article. The X-ray results and the chiral HPLC helped elucidate that compound 8 has an absolute configuration as 2R,3R,11bR. The crystal structure of racemic compound 5 contains two symmetry- independent molecules in the unit cell. Interestingly, while they are structural isomers, they are enantiomers, too, i.e., in solution, because they are not mirror images of each other in the crystal lattice. In order to elucidate the intermolecular interaction mechanism of the diastereomeric salt of compound 8, its crystal packing was investigated with regard to the weak interactions, such as salt bridge, OH...O and CH...O hydrogen bonds, and intermolecular CH...π interaction. The results showed that the carbonyl-assisted salt bridges and the OH...O hydrogen bonds formed polar columns in the crystal structure of the diastereomeric salt of compound 8, resembling butterflies with open wings as viewed along the c-axis. These polar columns were extended to three-dimensional network by intermolecular CH...O hydrogen bonds and intermolecular CH...π interactions.

Effects of anesthetics on vesicular monoamine transporter type 2 binding to 18F-FP-(+)-DTBZ: a biodistribution study in rat brain

OBJECTIVES The in vivo binding analysis of vesicular monoamine transporter type 2 (VMAT2) to radioligand has provided a means of investigating related disorders. Anesthesia is often inevitable when the investigations are performed in animals. In the present study, we tested effects of four commonly-used anesthetics: isoflurane, pentobarbital, chloral hydrate and ketamine, on in vivo VMAT2 binding to (18)F-FP-(+)-DTBZ, a specific VMAT2 radioligand, in rat brain. METHODS The transient equilibrium time window for in vivo binding of (18)F-FP-(+)-DTBZ after a bolus injection was firstly determined. The brain biodistribution studies under anesthetized and awake rats were then performed at the equilibrium time. Standard uptake values (SUVs) of the interest brain regions: the striatum (ST), hippocampus (HP), cortex (CX) and cerebellum (CB) were obtained; and ratios of tissue to cerebellum were calculated. RESULTS Isoflurane and pentobarbital did not alter distribution of (18)F-FP-(+)-DTBZ in the brain relative to the awake group; neither SUVs nor ratios of ST/CB and HP/CB were altered significantly. Chloral hydrate significantly increased SUVs of all the brain regions, but did not significantly alter ratios of ST/CB and HP/CB. Ketamine significantly increased SUVs of the striatum, hippocampus and cortex, and insignificantly increased the SUV of the cerebellum; consequently, ketamine significantly increased ratios of ST/CB and HP/CB. CONCLUSIONS It is concluded that in vivo VMAT2 binding to (18)F-FP-(+)-DTBZ are not altered by isoflurane and pentobarbital, but altered by chloral hydrate and ketamine. Isoflurane and pentobarbital may be promising anesthetic compounds for investigating in vivo VMAT2 binding. Further studies are warranted to investigate the interactions of anesthetics with VMAT2 binding potential with in vivo PET studies.

Synthesis and Biological Evaluation of 10‐11C‐Dihydrotetrabenazine as a Vesicular Monoamine Transporter 2 Radioligand

In this study, we synthesized a new carbon‐11‐labeled radiotracer, 10‐11C‐dihydrotetrabenazine (10‐11C‐DTBZ), and evaluated its potential as a vesicular monoamine transporter 2 (VMAT2) radioligand. The radiolabeled precursor 10‐O‐desmethyl‐dihydrotetrabenazine (10‐O‐desmethyl‐DTBZ) was prepared with a six‐step reaction using 3‐methoxy‐4‐benzyloxybenzaldehyde as starting material. 10‐11C‐DTBZ was synthesized by heating 1.0 mg of 10‐hydroxy precursor and 11C‐methyl iodide in the presence of 0.3 mL of dimethyl sulfoxide and 4.0 µL of 3 N KOH at room temperature for 3 min. After purification by solid phase extraction using an alumina Sep‐Pak cartridge, the final 10‐11C‐DTBZ product was obtained with a radiochemical purity of >99% and an uncorrected radiochemical yield of 18–26% (end of bombardment (EOB), n = 6). The overall synthesis time was approximately 20 min from the EOB to release of the product for quality control. Using small‐animal positron emission tomography (microPET), the striatum of normal rats was found to exhibit symmetrical labeling (STR/STL = 0.98 ± 0.05, n = 3) and the highest uptake of radioactivity (striatum/cerebellum, ST/CB = 2.89 ± 0.31 at 30–60 min, n = 3). In contrast, rats with 6‐hydroxydopamine unilateral lesions yielded asymmetrical striatal images with a higher 10‐11C‐DTBZ concentration on the unlesioned side (STunlesioned/CB = 2.53 ± 0.18, at 30–60 min, n = 3) compared with the lesioned side (STlesioned/CB = 1.26 ± 0.10, n = 3). These results suggest that 10‐11C‐DTBZ may represent a promising PET radiotracer for imaging VMAT2.

Structural requirement of C11b chirality of tetrabenazine analogs as VMAT2 imaging ligands: synthesis and in vivo evaluation

We studied on the structural requirement of C11b chirality of tetrabenazine (TBZ) analogs as vesicular monoamine transporter 2 (VMAT2) ligands. TBZ analogs (2, 6a, 6b) and 18F-radiolabeled [18F]6a and [18F]6b with eliminated C11b chirality were synthesized and characterized. Competition studies demonstrated that 2, 6a and 6b displayed much lower in vivo VMAT2 bindings than TBZ. MicroPET imaging studies of [18F]6a and [18F]6b showed negligible accumulation in VMAT2-enriched regions as compared with the known VMAT2 ligand 18F-FP-(+)-DTBZ. These results suggest that C11b chirality of TBZ analogs is essential for in vivo VMAT2 binding bioactivity.

A Concise Synthesis of Tetrabenazine and Its Crystal Structure

The title compound tetrabenazine was synthesized by reaction of 3-dimethyl-aminomethylheptan-2-one and 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride. This approach provides an efficient and concise way to the synthesis of the marketed drug tetrabenazine. The colorless single crystal of tetrabenazine suitable for X-ray analysis was obtained from saturated methanol solution. The X-ray results showed that tetrabenazine consists of (3R, 11bR) and (3S, 11bS) enantiomers. Two terminal methyl groups are disordered in the (3R, 11bR) enantiomer.

Synthesis and X-ray Analysis of Dihydrotetrabenazine, a Metabolite of Tetrabenazine

The dihydrotetrabenazine (DTBZ) was synthesized by reduction of tetrabenazine with sodium borohydride in ethanol. Crystals suitable for X-ray analysis were obtained from a mixed solution of dichloromethane and ethanol in a five-to-one volume ratio. The crystal is monoclinic, space group P21/c with crystallographic parameters: a = 15.0129(14) , b = 12.5677(12) , c = 9.7715(9) , β = 98.556(2)°, μ = 0.078 mm−1, V = 1823.1(3) 3, Z = 4, Dc = 1.164 g/cm3, F(000) = 696, T = 296(2) K. The X-ray analysis and the chiral HPLC show that the DTBZ prepared by our method consists of (2R,3R,11bR) and (2S,3S,11bS) enantiomers.

Synthesis and preliminary evaluation of 131I-9-iodovinyl-tetrabenazine targeting vesicular monoamine transporter 2

A new radioiodinated tetrabenazine (TBZ) derivative containing an iodovinyl group at 9-position of TBZ (131I-IV-TBZ, 11a) and the corresponding cold compound IV-TBZ (11b) were synthesized and characterized. Analysis of in vitro autoradiography with rat brain slices showed 11a has a high uptake in the striatum and the uptake could be blocked by known vesicular monoamine transporter 2 (VMAT2) inhibitor. Furthermore, 11b has a competitive binding to VMAT2. These results suggest that 11a has ability to bind to VMAT2 and the binding is specific. Further studies are warranted to assess this radioiodinated TBZ derivative for VMAT2 imaging in vivo.