Development of novel PET probe [¹¹C](R,R)HAPT and its stereoisomer [¹¹C](S,S)HAPT for vesicular acetylcholine transporter imaging: A PET study in conscious monkey

Abstract

Carbon-11-labeled (R,R)trans-8-methyl-2-hydroxy-3-[4-[2-aminophenyl]piperizinyl]-tetralin ([(11)C](R,R)HAPT) and its stereoisomer [(11)C](S,S)HAPT were developed for imaging vesicular acetylcholine transporters (VAChTs), exclusively located in presynaptic cholinergic neurons. Both positron emission tomography (PET) probes were evaluated in the brain of conscious monkey (Macaca mulatta) using high-resolution PET. Time-activity curves (TACs) of [(11)C](R,R)HAPT peaked within 5 min after the injection in all regions except the caudate and putamen, both of which showed peaks around 20 min postinjection. The regional distribution patterns of [(11)C](R,R)HAPT determined as total distribution volume (V(t)) were highest in the putamen, high in the caudate, intermediate in the amygdala, hippocampus, and thalamus, lower in the cingulate gyrus and frontal, temporal, and occipital cortices, and lowest in the cerebellum. In contrast, the distribution and TACs of [(11)C](S,S)HAPT were homogeneous in all regions. The uptake of [(11)C](R,R)HAPT was reduced by 1 mg/kg (-)-vesamicol, a specific VAChT antagonist, in all regions except the cerebellum, but not by 0.1 mg/kg SA4503, a specific sigma-1 receptor agonist. These results well reflect the in vitro affinity assessments using rat cerebral membranes. They also demonstrate that [(11)C](R,R)HAPT is a potential PET probe for noninvasive and quantitative imaging of VAChT in the living brain.

In Vivo Differences between Two Optical Isomers of Radioiodinated o-iodo-trans-decalinvesamicol for Use as a Radioligand for the Vesicular Acetylcholine Transporter

“…Thus, (-)-[ 125 I]OIDV bound to VAChT with higher affinity than (+)-[ 125 I]OIDV. However, the difference of binding property of [ 125 I]OIDV was fewer than that of [ 11 C]HATP[ 35 ] in vivo . That will be because the difference of binding affinity of two optical isomers of [ 125 I]OIDV to VAChT was fewer than that of [ 11 C]HATP.…”

“…In many cases, it is not uncommon for the optical isomers of a neuroreceptor agonist or antagonist to differ in their affinities and activities. As such, several radiolabeled vesamicol analogs developed for VAChT imaging have been shown to have one optical isomer having a higher affinity for VAChT than the other[ 31 , 34 , 35 ]. Therefore, to develop a superior VAChT imaging probe for SPECT, radiolabeled (-)-OIDV and (+)-OIDV were isolated and investigated for differences in their binding affinity and selectivity to VAChT, as well as their in vivo activities.…”

In Vivo and In Vitro Characteristics of Radiolabeled Vesamicol Analogs as the Vesicular Acetylcholine Transporter Imaging Agents

“…Although benzovesamicol (BV) has higher affinity and selectivity for VAChT than vesamicol, several benzovesamicol (BV) analogs were synthesized to improve VAChT affinity and to decrease the affinity for sigma receptors ( σ 1 and σ 2 ). A BV analog with phenylpiperazine instead of phenylpiperidine in BV ( 5 ) [ 51 , 52 ], a BV analog with benzylpiperidine instead of phenylpyridine ( 6 ), and a BV analog with pyridinyl piperidine instead of phenyl piperidine ( 7 ) showed a lower VAChT affinity than BV [ 53 ]. The affinity of 7 to the σ 1 receptor increased.…”

Kinetic modeling of [18F]VAT, a novel radioligand for positron emission tomography imaging vesicular acetylcholine transporter in non‐human primate brain

“…Nishiyama et al . () reported 11 C‐labeled ( R,R)‐trans ‐8‐methyl‐2‐hydroxy‐3‐[4‐[2‐aminophenyl]‐piperizinyl]tetralin ([ 11 C]( R,R )HAPT), a vesamicol derivative; PET imaging studies in non‐human primates (NHP) showed that this tracer can specifically bind to VAChT‐enriched regions, and time‐activity curves (TACs) of [ 11 C]( R,R )HAPT peaked within 20‐min post‐injection (Nishiyama et al . ).…”

“…Slow binding kinetics required a scan for approximately 6-h post-injection (Efange et al 2000;Giboureau et al 2007; Barret et al 2008;Mazere et al 2013). Nishiyama et al (2014) reported 11 C-labeled (R,R)-trans-8-methyl-2-hydroxy-3-[4- [2aminophenyl]-piperizinyl]tetralin ([ 11 C](R,R)HAPT), a vesamicol derivative; PET imaging studies in non-human primates (NHP) showed that this tracer can specifically bind to VAChTenriched regions, and time-activity curves (TACs) of [ 11 C](R,R) HAPT peaked within 20-min post-injection (Nishiyama et al 2014). However, it still bound to r 1/2 receptors with nanomolar affinity, resulting in only 10-fold selectivity for VAChT versus r 1/2 receptors (Kawamura et al 2006;Shiba et al 2006).…”