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. Author manuscript; available in PMC: 2014 Sep 20.
Published in final edited form as: Brain Res. 2013 Feb 27;1507:11–18. doi: 10.1016/j.brainres.2013.02.035

Autoradiographic evaluation of [3H]CUMI-101, a novel, selective 5-HT1AR ligand in human and baboon brain

J S Dileep Kumar a,b,*, Ramin V Parsey c, Suham A Kassir a, Vattoly J Majo b, Matthew S Milak a,b, Jaya Prabhakaran b, Mark D Underwood a,b, J John Mann a,b,d, Victoria Arango a,b
PMCID: PMC4169296  NIHMSID: NIHMS620831  PMID: 23454434

Abstract

[11C]CUMI-101 is the first selective serotonin receptor (5-HT1AR) partial agonist radiotracer for positron emission tomography (PET) tested in vivo in nonhuman primates and humans. We evaluated specific binding of [3H]CUMI-101 by quantitative autoradiography studies in postmortem baboon and human brain sections using the 5- HT1AR antagonist WAY100635 as a displacer. The regional and laminar distributions of [3H]CUMI-101 binding in baboon and human brain sections matched the known distribution of [3H]8-OH-DPAT and [3H]WAY100635. Prazosin did not measurably displace [3H]CUMI-101 binding in baboon or human brain sections, thereby ruling out [3H]CUMI-101 binding to α1-adrenergic receptors. This study demonstrates that [11C]CUMI-101 is a selective 5-HT1AR ligand for in vivo and in vitro studies in baboon and human brain.

Keywords: 5-HT1AR, brain, serotonin agonist, autoradiography

1. Introduction

Serotonin1A receptors (5-HT1AR) have been implicated in the pathophysiology of mood and anxiety disorders, suicidal behavior, sexual functions, eating and panic disorders, epilepsy, schizophrenia, Parkinson’s disease and Alzheimer’s disease as well as in the mechanism of action of antidepressants (Akimova et al., 2009; Drago et al., 2008; Elliott et al., 2009; Giovacchini et al., 2009; Munoz et al., 2009; Richardson-Jones et al., 2010).

There are several radioligands for the in vivo and in vitro quantification of 5-HT1AR. Most tracers belong to two structural families: (i) compounds with structural similarity to the 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (e.g. WAY-100635); or (ii) derivatives of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (Kumar and Mann, 2007; Pike et al., 2001). Among these, [3H] or [11C] labeled WAY-100635 has been the most commonly used 5-HT1AR antagonist ligand (Assem-Hilger et al., 2010; Saijo et al., 2010; Sargent et al., 2010; Stein et al., 2008). WAY-100635 has more than 100-fold selectivity for 5-HT1AR versus other receptors except for 5-HT2B, adrenergic α1A and dopamine D4 receptors (Chemel et al., 2006). The discovery of (±)8-OH-DPAT as a 5-HT1AR agonist revolutionized 5-HT1AR research (Duncan et al., 1998; Simpson et al., 1996; Trillat et al., 1998). Although additional radioligands have been reported over the years, [3H]8-OH DPAT remains the most widely used agonist radioligand for in vitro quantification of 5-HT1AR sites, despite its moderate affinity for some non-5-HT1A targets including 5-HT7R, 5-HT1B/DR, α2-adrenergic receptor (α2-AR), D2-like receptors and the serotonin transporter (Heusler et al., 2010; Nenonene et al., 1994; Sprouse et al., 2004). As a result, [3H]8-OH-DPAT binding in 5-HT1AR knockout mice has detectable binding to 5-HT7R and α2-AR. [3H]8-OH-DPAT also binds to serotonin transporters in striatum and the raphe nuclei (Assié and Koek, 2000; Schoemaker and Langer, 1986). In vivo, 8-OH-DPAT and its derivatives have failed as PET tracers due to poor blood brain barrier (BBB) penetration or high nonspecific binding (Kumar and Mann, 2007). Thus, a reliable comparison of in vitro vs. in vivo distribution of 5-HT1AR binding sites is not possible due to the lack of a ligand works both in vivo and in vitro.

We have developed [O-Methyl-11C]2-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4- methyl-1,2,4-triazine-3,5(2H,4H)dione ([11C]CUMI-101; Figure 1) and reported its properties as a specific 5-HT1AR partial agonist PET tracer in human and nonhuman primates (Kumar et al., 2012; Kumar et al., 2011; Kumar et al., 2007; Milak et al., 2008; Milak et al., 2010; Milak et al., 2011). Compared to 8-OH-DPAT, CUMI-101 has higher affinity (Ki= 0.15 nM), better selectivity for 5-HT1AR, and it is a partial agonist (Emax = 88%; EC50 = 0.1 nM, Kumar et al., 2007). It therefore has the potential to be both a PET tracer and when tritiated, a ligand for in vitro studies. This would allow for direct comparison of in vitro and in vivo findings with the same ligand.

Figure 1.

Figure 1

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Chemical structure of [3H]CUMI-101

A detailed study of the characteristics of CUMI-101 as a 5-HT1AR ligand in vitro has not been published. We therefore carried out such a study using [3H]CUMI-101. We believe, that in addition to having a superior pharmacological profile, [3H]CUMI-101 offers several other advantages over [3H]8-OH-DPAT including: 1. ease of synthesis; 2. minimal autoradiolysis; 3. possibility of measurement of endogenous competition with intrasynaptic serotonin; 4. comparison of in vivo human/animal data obtained from PET studies and in vitro postmortem data in human/animal brain using [11C]CUMI-101 and [3H]CUMI-101 respectively; 5. quantification of the high affinity (HA) state of the receptor; and 6. a useful tool for agonist drug development and pharmacology studies based on 5-HT1AR. Herein we report quantitative receptor autoradiography data of regional, specific binding of [3H]CUMI-101 to postmortem human and baboon brain sections, as well as the absence of α1-adrenergic receptor (α1-AR) binding.

2. RESULTS

Binding of [3H]CUMI-101 to baboon brain

The regional distribution of [3H]CUMI-101 binding is shown in Figure 2. [3H]CUMI-101 binding to 5-HT1A sites varied across brain regions. The highest binding density was found in the pyramidal layer of CA1 of the hippocampus (86.0±1.8 fmol/mg tissue), followed by the molecular layer of the dentate gyrus (47.3±0.8 fmol/mg tissue), layer II of prefrontal cortex (45.2±5.1 fmol/mg tissue) and most other neocortical areas, including the insular cortex (41.1±1.9 fmol/mg tissue). Other regions had less binding: the total thickness of gray matter (when all 6 cortical layers are measured together) in frontal cortex (28.1±1.8 fmol/mg tissue), claustrum (23.7±3.9 fmol/mg tissue), amygdala (20.4±3.1 fmol/mg tissue), striatum (7.7±3.0 fmol/mg tissue), thalamus (3.1±3.1 fmol/mg tissue) and cerebellum (1.4±1.2 fmol/mg tissue).

Figure 2.

Figure 2

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Autoradiograms of [3H]CUMI-101 binding to baboon brain sections. Total binding was defined with [3H]CUMI-101 (images A, C, E, and G) and nonspecific binding of [3H]CUMI-101 was determined in presence of WAY100635 (images B, D, F, and H). Amyg: Amygdala; CA1-PL: CA1 pyramidal layer; Caud: Caudate Nucleus; Cb: Cerebellum; Claust: Claustrum; DG-ML: Dentate Gyrus Molecular Layer; Ins: Insula, PFC-LII: Prefrontal cortex layer II, Put: Putamen; Thal: Thalamus

We also carried out autoradiography studies of [3H]8-OH-DPAT in baboon brain from the same animal and the results are quite comparable to [3H]CUMI-101 binding in the tested regions (Figures 2 and 4). Figure 5 shows the high correlation of binding of the two ligands across brain regions (R2=0.94). In terms of relative levels of binding, CA1 pyramidal layer, DG-molecular layer and insular layer II have comparable binding for both radioligands, but [3H]CUMI-101 has higher binding than [3H]8-OH-DPAT in the other tested brain regions.

Figure 4.

Figure 4

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Autoradiograms of [3H]8-OH-DPAT binding to baboon brain sections. PFC-Gr: Prefrontal cortex grey; PFC-LII: Prefrontal cortex-layer II: Ins-LII: Insula Layer II, Caud: Caudate Nucleus, Put: Putamen, Claust: Claustrum, Cx-LII Cortex layer II, Cx-Gr: Cortex grey, Thal: Thalamus, DG-ML: Dentate Gyrus-Molecular Layer, CA1-PL: CA1-pyramidal Layer.

Figure 5.

Figure 5

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Correlation of [3H]CUMI-101 and [3H]8-OH-DPAT binding in baboon brain. CA1-PL: CA1- Pyramidal Layer, DG-ML: Dentate Gyrus-Molecular Layer, FC-LII: Frontal cortex Layer II, Ins-LII: Insula Layer II, PFC-LII: Prefrontal cortex-layer II

Binding of [3H]CUMI-101 to postmortem human brain

Figure 6 shows autoradiograms of [3H]CUMI-101 binding to human brain sections. As in the baboon brain, binding is highest in pyramidal layer of CA1 (96.5±1.6 fmol/mg tissue), followed by molecular layer of DG (43.3±5.7 fmol/mg tissue), layer II of insula (44.5±3.0 fmol/mg tissue) layer II of prefrontal cortex (39.7±1.3 fmol/mg tissue) and claustrum (25.5±2.5 fmol/mg tissue). Amygdala has intermediate levels of binding (8.1±1.3 fmol/mg tissue). The cerebellar vermis (2.0±0.4 fmol/mg tissue) and cerebellar cortex have lower binding (0.65±0.9 fmol/mg tissue), whereas, thalamus (1.4±0.4 fmol/mg tissue) and striatum (0.5±0.3 fmol/mg tissue) have the least tracer binding (Figure 7). The specific binding of [3H]CUMI-101 was determined by 1 μM WAY100635, and non-specific binding in all areas is low (<10%). Autoradiography results in human brain sections of the same subjects using [3H]8-OH-DPAT are comparable with [3H]CUMI-101 binding. Figure 8 shows correlation of [3H]8-OH-DPAT and [3H]CUMI-101 binding in tested brain regions (R2= 0.92). Both radioligands show comparable binding in CA1 pyramidal layer, insular layer II and claustrum. [3H]CUMI-101 shows higher binding in DG-molecular layer, whereas, [3H]8-OH-DPAT shows higher binding in PFC-layer II and amygdala.

Figure 6.

Figure 6

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Autoradiograms of [3H]CUMI-101 total (A, B, C, G, H, I) and nonspecific binding in presence of WAY100635 (D, E, F, J, K, L) in human brain sections. Amyg: Amygdala; CA1-PL: CA1 pyramidal layer; Caud: Caudate nucleus; Cb-Cx: Cerebellar Cortex; Cb–Verm: Cerebellar Vermis; Claust: Claustrum; DG-ML: Dentate Gyrus, Molecular Layer; Ins LII: Insula Layer II, PFC-LII: Prefrontal cortex layer II, Put: Putamen; Thal: Thalamus

Figure 7.

Figure 7

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[3H]CUMI-101 binding to 5-HT1AR and α1-AR in human brain. Cer-Cx: Cerebellar cortex, Cer-Verm: Cerebellar vermis, CA1-PL: CA1 pyramidal layer, DG-ML: Dentate Gyrus Molecular Layer, Ins LII: Insula Layer II, PFC-LII: Prefrontal cortex layer II

Figure 8.

Figure 8

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Correlation of [3H]CUMI-101 and [3H]8-OH-DPAT binding in human brain. CA1-PL: CA1 pyramidal layer, DG-ML: Dentate Gyrus Molecular Layer, Ins LII: Insula Layer II, PFC-LII: Prefrontal cortex layer II

α-1AR binding of [3H]CUMI-101 in postmortem baboon and human brain

CUMI-101 binding affinity for α1-AR (Ki = 6.75 nM) is 45 times less than the affinity for the 5-HT1AR (Ki = 0.15 nM) (Kumar et al, 2006). Nevertheless, we determined the proportion of binding across baboon brain regions to α1-AR by autoradiography using 1 μM of prazosin to displace [3H]CUMI-101 binding (Figure 3). There was no detectable α1-AR binding in brain regions with reportedly abundant α1-AR such as thalamus, cortical regions, striatum, amygdala, and cerebellum, suggesting that [3H]CUMI-101 does not bind to α1-AR. The molecular layer of the dentate gyrus showed the highest displacement with prazosin corresponding to a binding of 2.7±.4 fmol/mg tissue (Figure 3). In agreement with baboon data, prazosin (1 μM) on human brain sections did not result in any statistically significant reduction of [3H]CUMI-101 binding, indicating no measurable specific binding to α1-AR (Figure 7). However, in contrast with baboon, the molecular layer of the human dentate gyrus shows 6.5 fmol/mg tissue binding in prazosin displacement studies.

Figure 3.

Figure 3

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Autoradiograms of [3H]CUMI-101 binding to 5-HT1AR and α1-AR in baboon brain. Amyg: Amygdala, CA1-PL: CA1-pyramidal Layer, DG-ML: Dentate Gyrus- Molecular Layer, PFC-LII: Prefrontal cortex layer II, Ins LII: Insular cortex layer II, FC: Frontal cortex

3. DISCUSSION

CUMI-101 is a high affinity partial agonist for 5-HT1AR and its C-11 analogue is the only PET ligand currently available for the in vivo quantification of high affinity 5-HT1AR in human and nonhuman primates (Kumar et al., 2009, Hines et al., 2011; Milak et al., 2010; Milak et al., 2011, Selvaraj et al. 2012, Kumar et al. 2012). The present study examined the binding characteristics of [3H]CUMI-101 in postmortem brain sections of human and baboon using quantitative autoradiography and found the pattern of relative regional brain radioligand binding in the tested regions is comparable to previously reported binding of [3H]8-OH-DPAT and [3H]WAY100635 (Burnet et al., 1997). Moreover, the in vitro data obtained for [3H]CUMI-101 in the tested brain regions are in agreement with in vivo data obtained for [11C]CUMI-101 in human (Milak et al, 2010) with PET. The highest in vivo binding for [11C]CUMI-101 in human was found in entorhinal cortex, followed by hippocampus, and cortical regions which is similar to in vivo findings in baboon. We find that the striatum, thalamus and cerebellum show the least in vitro binding, and this is also the case for in vivo binding in human (Milak et al, 2010).

We examined whether [3H]CUMI-101 binds to α1-AR in baboon and human brain by evaluating binding of [3H]CUMI-101 in human and baboon brain in vitro and found 1 μM of prazosin did not cause statistically significant blockade of binding in the tested brain regions except in the DG-molecular layer of the hippocampus where a small level of binding was detected. Prazosin did not displace [3H]CUMI-101 binding in α1-AR rich areas such as claustrum, thalamus, cerebral cortex, striatum or cerebellum. Hence the DG-molecular layer binding based on prazosin displacement is not likely due to α1-AR binding. Since the α1-AR antagonist prazosin produces cardiovascular changes in monkeys even at a 0.01 mg/kg dose (Schindler at al., 1992), we did not perform blocking studies in vivo in baboons to test the α1-AR selectivity of [11C]CUMI-101 as cardiovascular changes themselves can alter the binding outcome with PET (Ohira et al., 2011), and larger doses of prazosin could threaten the health of baboons under anesthesia. One in vivo study in rodents and monkeys with [11C]CUMI-101 reported binding in thalamus and cerebellum, which was partially displaced with prazosin; that binding was attributed to α1-AR and 5HT1AR binding in these brain regions in these particular species (Liow at al, 2010). It has been reported that brain α1-AR regional distribution in mammals is species dependent (Szot et al 2005, Palaclos et al. 1987). As described above, our studies indicate no significant α1-AR binding in the tested brain regions in either baboon or human, and perhaps species differences are the explanation for the discrepancies with the literature.

The high specific/nonspecific binding ratio of [3H]CUMI-101 in all brain regions tested in human and baboon compared favorably with [3H]8-OH-DPAT, indicating CUMI-101 is an alternative ligand for in vitro studies. This would also allow for results from in vitro studies with [3H]CUMI-101 to be more directly comparable to in vivo PET studies with [11C]CUMI-101. The minimal binding to α1-AR in baboon and human brain indicates [3H]CUMI-101 is a sensitive tool for in vitro and [11C]CUMI-101 for in vivo studies in baboon and human to quantify high affinity 5-HT1AR in the central nervous system.

4. Materials and Methods

The use of human samples for this study were approved by the Institutional Review Board of the New York State Psychiatric Institute (NYSPI) and were determined to be non-human subjects research. Postmortem sections from two nonpsychiatric control human brains (20μm) that included prefrontal cortex, striatum, amygdala, hippocampus, cerebellum and thalamus were used. Baboon brain (20 μm) sections from prefrontal, midcallosal and cerebellum anatomical levels containing the regions of interest were used for in vitro studies. [3H]CUMI-101 (NIMH Code: M-906) was obtained from the NIMH drug supply program. [3H]8-OH-DPAT was purchased from Sigma Life Science. Prazosin hydrochloride and WAY100635 maleate were purchased from Tocris and RBI, respectively.

Tissue sections were incubated in Tris-Sucrose buffer (pH 7.6) containing 170mM Tris-HCl, 4mM CaCl2, 138 mM sucrose 2 nM 3H-CUMI-101 (Specific Activity 77.7 Ci/mmol) for 60 min at 37°C. Adjacent sections were incubated with 2 nM 3H-CUMI and 1μm prazosin or 1μm WAY 100635 to determine specific binding to α1-AR and 5-HT1ARs, respectively. Sections were washed for 10 minutes (2 X 5) minutes in Tris-Sucrose buffer at 4°C followed by a dip in cold distilled H2O to remove buffer salts. Sections were then dried under a stream of desiccated cold air, dried and exposed to 4% paraformaldehyde vapor over night. Slides were exposed to tritium-sensitive screen (Fuji) for three days, alongside 3H-containing polymer standards (ART-123 and -123A from American Radiolabeled Chemicals, Inc.) and developed using a Packard Cyclone phosphor imager. All slides were laid out in X-ray film cassettes and exposed to Biomax MS film (Kodak) for 6 weeks, developed using Kodak D-19 developer and fixative. The autoradiograms were sampled using a computer-based image analysis system (MCID, Imaging Research Inc., St. Catharines, Ontario, Canada) as previously described (Arango et al., 1993; Arango et al., 1995; Boldrini et al., 2008). All the sections were corrected for light transmission inhomogeneities and the known nCi/mg values from the standards slides were half-life corrected, and converted to femtomoles of radioligand per unit mass of tissue.

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