High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

Abstract

The serotonin 5-HT1B receptors regulate the release of serotonin and are involved in various disease states, including depression and schizophrenia. The goal of the study was to evaluate a high affinity and high selectivity antagonist, [11C]P943, as a PET tracer for imaging the 5-HT1B receptor. [11C]P943 was synthesized via N-methylation of the precursor with [11C]methyl iodide or [11C]methyl triflate using automated modules. The average radiochemical yield was approx. 10% with radiochemical purity of >99% and specific activity of 8.8 ± 3.6 mCi/nmol at the end-of-synthesis (n = 37). PET imaging was performed in non-human primates with a High Resolution Research Tomograph (HRRT) scanner with a bolus/infusion paradigm. Binding potential (BPND) was calculated using the equilibrium ratios of regions to cerebellum. The tracer uptake was highest in the globus pallidus and occipital cortex, moderate in basal ganglia and thalamus, and lowest in the cerebellum, which is consistent with the known brain distribution of 5-HT1B receptors. Infusion of tracer at different specific activities (by adding various amount of unlabeled P943) reduced BPND values in a dose-dependent manner, demonstrating the saturability of the tracer binding. Blocking studies with GR127935 (2 mg/kg, IV), a selective 5-HT1B/5-HT1D antagonist, resulted in reduction of BPND values by 42-95% across regions; for an example, in occipital region from 0.71 to 0.03, indicating a complete blockade. These results demonstrate the saturability and specificity of [11C]P943 for 5HT1B receptors, suggesting its suitability as a PET radiotracer for in vivo evaluations of the 5-HT1B receptor system in humans.

Determination of the In Vivo Selectivity of a New κ-Opioid Receptor Antagonist PET Tracer 11C-LY2795050 in the Rhesus Monkey

“…at end of synthesis was 24.6 ± 14.3 MBq/nmol (n = 14). Synthesis of [ 11 C]carfentanil was carried out with an AutoLoop (Bioscan, Washington,DC, USA), in a procedure similar to that used for the synthesis of [ 11 C]P943 (20). In brief, a solution of 0.5–1.0 mg of desmethyl carfentanil precursor in 80–90 μL of anhydrous DMSO and 2.5 μL of 1N CsOH in MeOH was loaded unto a stainless steel loop and reacted with [ 11 C]MeOTf for 5 min at room temperature.…”

Normative database of the serotonergic system in healthy subjects using multi-tracer PET

“…[ 11 C]P943 (R-1-[4-(2-methoxy-isopropyl)-phenyl]-3-[2-(4-methylpiperazin-1-yl)benzyl]-pyrrolidin-2-one) binds with high affinity to the 5-HT 1B receptors (Gallezot et al, 2010;Nabulsi et al, 2010). [ 11 C]P943 was prepared at the Department of Diagnostic Radiology, Yale University, New Haven.…”

“…The PET scans were acquired for 120 min on an HRRT PET scanner (207 slices, resolution less than 3 mm full-width at half maximum in 3D acquisition mode). PET image acquisition and image reconstruction were performed as described previously (Gallezot et al, 2010;Nabulsi et al, 2010).…”

“…5-HT 1B receptors are located presynaptically on both serotonergic neurons as autoreceptors and on non-serotonergic neurons as heteroreceptors (Boschert et al, 1994;Clark and Neumaier, 2001;Sari et al, 1999), where they are involved in the release of a range of neurotransmitters such as serotonin (Martin et al, 1992), dopamine (Sarhan et al, 1999), acetylcholine (Maura and Raiteri, 1986), glutamate (Muramatsu et al, 1998), noradrenaline (Hoyer et al, 1990) and GABA (Bramley et al, 2005;Tanaka and North, 1993). So far two 5-HT 1B radioligands, [ 11 C]P943 (Gallezot et al, 2010;Nabulsi et al, 2010) and [ 11 C]AZ10419369 (Varnäs et al, 2011), suitable for human PET imaging have been developed to study the function of these receptors in vivo and to investigate their role in the pathophysiology of neuropsychiatric disorders. The 5-HT2 receptor group includes excitatory receptors.…”

Preclinical Pharmacology and Pharmacokinetics of AZD3783, a Selective 5-Hydroxytryptamine 1B Receptor Antagonist

“…Selective 5-HT 1B antagonists such as (R)-N- [5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (AR-A000002) (Hudzik et al, 2003) and 1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2Ј-methyl-4Ј-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride (SB-616234-A) (Dawson et al, 2006) have been shown to elevate serotonergic neurotransmission in vivo and exhibit effects indicative of antidepressant and anxiolytic properties in animals. The discovery of selective, high-affinity 5-HT 1B compounds made it possible to develop 5-HT 1B -specific ligands for positron emission tomography (PET) to obtain noninvasive quantification of specific binding to the receptor in brain (Pierson et al, 2008;Nabulsi et al, 2010). These tools can provide an understanding of the level of receptor occupancy required for minimal and maximal efficacy and the margin to on-target side effects that is critical for formulating a testable translational pharmacology hypothesis for early human testing.…”