Synthesis and preliminary evaluation of an iodovinyl‐tetrabenazine analog as a marker for the vesicular monoamine transporter

Abstract

SUMMARYA derivative of tetraknazine ("BZ, 1) containing an iodovinyl group (I-TBZ, was prepared as a potential radiotracer for the vesicular monoamine transporter. The synthesis of h was achieved by ethynylation of TBZ. The ethynyl derivative 4, was converted to the corresponding vinylstannane z. [W'JI-TBZ can readily cross the blood brain barrier and localize in the brain (0.92 and 0.36 % dose/organ, at 2 min and 30 min, respectively). However, no specific regional uptake of the ligand was observed. Subsequent biodistribution studies performed using two well resolved peaks obtained from chiral HPLC separation of a, demonstrated that Fraction I displayed higher brain uptake (0.6 % dose/organ. 20 min) than the latter peak (Fraction 11, 0.3 8 doselorgan, 20 min). Fraction I also exhibited a modest degree of specificity for the striaturn which could be blocked by pretreatment with tetraknazine. The high lipophilicity of & (PoIb for Fraction 1 and I1 = 1723 and 1395. respectively) may contribute to high nonspecific binding in vivo, and result in the low targednontarget ratio observed for this compound.Iodovinyl-TBZ analog a is a poor candidate as a SPECT imaging agent for the vesicular monoamine transporter.

Vesicular monoamine transporter 2: Role as a novel target for drug development

“…104 , 114-117 Lobeline inhibits nicotine-evoked [ 3 H]DA overfl ow from rat striatal slices with an IC 50 of 1 μM, suggesting that lobeline acts as an antagonist at nicotinic receptors mediating nicotine-evoked DA release (ie, a 6 b 2 b 3* subtype). 116 Lobeline also inhibits nicotine-evoked 86 Rb + effl ux from rat thalamic synaptosomes with an IC 50 of 0.7 μM, indicating that lobeline is also an antagonist at a 4 b 2* nicotinic receptors. 116 Moreover, lobeline also inhibits [ 3 H]methyllycaconitine binding to rat brain membranes with a K i of 6.26 μM, indicating that there is an interaction with the a 7* nicotinic receptor subtype.…”

“…Thus, compound 10 ( Figure 4 ), in which an 125 I atom has been introduced for autoradiographic studies of VMAT2, has been synthesized. 86 ( ± )-Compound 10 can be separated by chiral HPLC into its optical isomers, and the fi rst eluted enantiomer binds to VMAT2 with a K d of 0.22 nM. 87 Structure-activity relationship (SAR) studies involving TBZ analogs have shown that quaternization of the amine nitrogen at position 5, aromatization of ring C, and elimination of the carbonyl group afforded compounds that were devoid ( 3a-d ).…”

Vesicular monoamine transporters: Structure‐function, pharmacology, and medicinal chemistry

“…A derivative of TBZ containing a 2-iodovinyl group [ 125 I-VTBZ;Table VII ( 87 )] was tested as a possible SPECT agent81. Following i.v.…”

Binding of 125I‐iodovinyltetrabenazine to CNS vesicular monoamine transport sites

“…Structure-activity studies involving TBZ derivatives reported previously suggest that the analogs containing considerable steric bulk at the 2-position retain monoamine depleting activity andlor high affinity for the VMAT sites (Kaiser and Setler, 1981;Neumeyer, 1981;. The addition of an iodovinyl group at the 2-position resulted in the derivative iodovinyltetrabenazine (I-TBZ) (Canney et al, 1993). This molecule was success- fully radiolabeled with 1-125 and 1-123, and it was subsequently resolved into two fractions (Fraction I and Fraction 11) with a chiral HPLC separation (Canney et al, 1993).…”