Derivatization of (±) dihydrotetrabenazine for copper-64 labeling towards long-lived radiotracers for PET imaging of the vesicular monoamine transporter 2

Abstract

Dihydrotetrabenazine (DTBZ) derivatized from (+) Tetrabenazine (TBZ) has been used for imaging the expression of VMAT2 when labeled with 11C (t1/2 = 20.3 min.) or 18F (t1/2 = 110 min.) in neurodegenerative diseases or pancreatic beta-cell. Because 11C or 18F radiolabels are only available in the proximity of a biomedical cyclotron facility, here we report our work of derivatizing (+) and (−) DTBZ using a 64Cu-specific bifunctional chelator scaffold (64Cu: t1/2 = 12.7 h) for the preparation of long-lived VMAT2 targeted radiotracers, 64Cu-CB-TE2A-(+)-DTBZ and 64Cu-CB-TE2A-(−)-DTBZ. The specific VMAT2 binding affinity of 64Cu-CB-TE2A-(+)-DTBZ measured using rat brain homogenate or porcine islets was not compromised by our chemical modifications while that of its (−) counterpart remained low as in 11C or 18F labeled (±) DTBZ.

Imaging pancreatic islet cells by positron emission tomography

“…Currently, there have only been limited reports using other PET nuclides. Recently, Kumar et al[ 44 ] reported synthesis of the 64 Cu-specific bifunctional chelator scaffold DTBZ analogues: 64 Cu-CB-TE2A-(+)-DTBZ (IC 50 = 16.8 ± 6.9 nmol/L) and 64 Cu-CB-TE2A-(-)-DTBZ (IC 50 = 253.2 ± 107.8 nmol/L). As we knew that, the IC 50 values of (+)-DTBZ and (-)-DTBZ were 0.97 ± 0.48 nmol/L and 2.2 ± 0.3 μmol/L, respectively[ 45 ].…”

“…As we knew that, the IC 50 values of (+)-DTBZ and (-)-DTBZ were 0.97 ± 0.48 nmol/L and 2.2 ± 0.3 μmol/L, respectively[ 45 ]. The VMAT2 specific binding affinity of 64 Cu-CB-TE2A-(+)-DTBZ was not compromised by their chemical modifications, while that of its (-) counterpart remained low as in 11 C- or 18 F-labeled (±) DTBZ[ 44 ]. Currently, there are no further reports on PET imaging using 64 Cu-CB-TE2A-(+)-DTBZ in animal studies.…”

Synthesis of (±)-Tetrabenazine by Visible Light Photoredox Catalysis

“…The value of these compounds extends beyond the treatment of hyperkinetic disorders. The high VMAT2 affinity of (+)-(2 R ,3 R ,11b R )-DTBZ ( K i 0.97 nM) has spurred the development of radiolabeled analogues that are valuable imaging agents for diagnosing neurological conditions. − Furthermore, Parkinsonian tremors can be modeled by dosing rodents with TBZ to induce tremulous jaw movements …”