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

Dihydrotetrabenazine (DTBZ) derivatized from (+) Tetrabenazine (TBZ) has been used for imaging the expression of VMAT2 when labeled with ¹¹C (t_1/2 = 20.3 min) or ¹⁸F (t_1/2 = 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: t_1/2 = 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.