In vivo kinetics and displacement study of a carbon-11-labeled hallucinogen, N,N-[11C]dimethyltryptamine

The endogenous hallucinogen, N,N-dimethyltryptamine (DMT), was labeled with carbon-11 and its regional distribution in rat brain studied. [11C]DMT showed higher accumulation in the cerebral cortex, caudate putamen, and amygdaloid nuclei. Studies of the subcellular distribution of [11C]DMT revealed the specific localization in the fractions enriched with serotonin receptors only when a very low dose was injected into rats. The proportions of the radioactivity in receptor-rich fractions were greatly enhanced by pretreatment with the monoamine oxidase inhibitor, pargyline. Specific binding of [11C]DMT to serotonin receptors in dog brain was demonstrated by a positron emission tomographic study in which 5-methoxy-N,N-dimethyltryptamine caused approximately 20% displacement of the radioligand from the receptors.     

11C-labeling of indolealkylamine alkaloids and the comparative study of their tissue distributions

Five indolealkylamines (N,N-dimethyltryptamine, N-methyltryptamine, bufotenine, O-methylbufotenine, N,N,N-trimethyltryptamine iodide) were labeled with 11C by use of 11CH3I. The labeled compounds were synthesized with a radiochemical yield of 2-50% (based on trapped 11CH3I) in 20-35 min with radiochemical purities of more than 92%. The tissue distributions of these labeled compounds were investigated in rats. In all cases, the accumulations in the liver, lung and small intestine were high. [11C]DMT and [11C]OMB also accumulated to a large extent in the brain, where their accumulation was retained. Brain uptake of three other radiopharmaceuticals was low. [11C]DMT is the radiopharmaceutical of choice for the study of the serotonin action mechanism in the brain, because it has the highest radiochemical yield and the highest brain uptake of these 11C-labeled compounds.     

In vivo imaging of adenosine A2A receptors in rat and primate brain using [11C]SCH442416

Purpose The aim of this study was to evaluate the suitability of [¹¹C]SCH442416 for the in vivo imaging of adenosine A_2A receptors.Methods In rats and Macaca nemestrina, we evaluated the time course of the cerebral distribution of [¹¹C]SCH442416. Furthermore, in rats we investigated the rate of metabolic degradation, the inhibitory effects of different drugs acting on adenosine or dopamine receptors and the modification induced by the intrastriatal administration of quinolinic acid (QA).Results The rate of metabolic degradation of [¹¹C]SCH442416 in rats was slow; 60 min after tracer injection, more than 40% of total plasma activity was due to unmetabolised [¹¹C]SCH442416. At the time of maximum uptake, radioactive metabolites represented only 6% of total extractable activity in the cerebellum and less than 1% in the striatum. In the striatum, the region with the highest expression of A_2A receptors, the in vivo uptake of [¹¹C]SCH442416 was significantly reduced only by drugs acting on A_2A receptors or by QA, a neurotoxin that selectively reduces the number of intrastriatal GABAergic neurons. Position emission tomography (PET) studies in monkeys indicated that the tracer rapidly accumulates in brain, reaching maximum uptake between 5 and 10 min. Twenty minutes after the injection, radioactivity concentration in the striatum was two times that in the cerebellum.Conclusion The specificity of binding, the rank order of regional distribution in the brain of rats and M. nemestrina, the good signal to noise ratios and the low amount of radioactive metabolites in brain and periphery indicate that [¹¹C]SCH442416 is a promising tracer for the in vivo imaging of A_2A adenosine receptors using PET.     

Shortened protocol in practical [11C]SA4503-PET studies for sigma1 receptor quantification

In practical positron emission tomography (PET) diagnosis, a shortened protocol is preferred for patients with brain disorders. In this study, the applicability of a shortened protocol as an alternative to the 90-min PET scan with [¹¹C]SA4503 for quantitative sigma₁ receptor measurement was investigated. Tissue time-activity curves of 288 regions of interest in the brain from 32 [¹¹C]SA4503-PET scans of 16 healthy subjects prior to and following administration of a selective serotonin reuptake inhibitor (fluvoxamine or paroxetine) were applied to two algorithms of quantitative analysis; binding potential (BP) was derived from compartmental analysis based on nonlinear estimation, and total distribution volume (tDV) was derived from Logan plot analysis. As a result, although both BP and tDV tended to be underestimated by the shortened method, the estimates from the shortened protocol had good linear relationships with those of the full-length protocol. In conclusion, if approximately 10% differences in the estimated results are acceptable for a specific purpose, then a 60-min measurement protocol is capable of providing reliable results.     

Characteristics of specific in vivo labeling of neuroleptic binding sites with 3-N-[11C]methylspiperone

In vivo binding of 3-N-[¹¹C]methylspiperone ([¹¹C]NMSP) was saturable in the rat forebrain, but not in the cerebellum. Nonspecific binding was almost equivalent in all brain regions except for the white matter. [¹¹C]NMSP binding was localized to receptor-rich fractions when low doses were administered (less than 20 nmol/kg body weight). The striatum-to-cerebellum ratio was a function of time after injection and administered dose. This radio remained constant in low doses of under 30 nmol/kg. The radioactivity curve of the cerebellum in a control positron-emission tomographic study almost equaled that of the striatum in the dog pretreated with spiperone (2 mg). This indicates that the amount of binding in the cerebellum might be considered a nonspecific binding and unbound pool. The data obtained by the pretreatment study was different from that of displacement, which suggested that displaceable [¹¹C]NMSP in the specific binding sites of the striatum was not completely cleared from the brain tissue by a large amount of unlabeled spiperone.     

Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [<Superscript>11</Superscript>C]PE2I

Purpose We aimed to determine the composition of radioactivity in rat brain after intravenous administration of the dopamine transporter radioligand, [¹¹C]PE2I. Methods PET time-activity curves (TACs) and regional brain distribution ex vivo were measured using no-carrier-added [¹¹C]PE2I. Carrier-added [¹¹C]PE2I was administered to identify metabolites with high-performance liquid radiochromatography (RC) or RC with mass spectrometry (LC-MS and MS-MS). The stability of [¹¹C]PE2I was assessed in rat brain homogenates. Results After peak brain uptake of no-carrier-added [¹¹C]PE2I, there was differential washout rate from striata and cerebellum. Thirty minutes after injection, [¹¹C]PE2I represented 10.9 ± 2.9% of the radioactivity in plasma, 67.1 ± 11.0% in cerebellum, and 92.5 ± 3.2% in striata, and was accompanied by two less lipophilic radiometabolites. [¹¹C]PE2I was stable in rat brain homogenate for at least 1 h at 37°C. LC-MS identified hydroxylated PE2I (1) (m/z 442) and carboxyl-desmethyl-PE2I (2) (m/z 456) in brain. MS-MS of 1 gave an m/z 442→424 transition due to H₂O elimination, so verifying the presence of a benzyl alcohol group. Metabolite 2 was the benzoic acid derivative. Ratios of ex vivo measurements of [¹¹C]PE2I, [¹¹C]1, and [¹¹C]2 in striata to their cognates in cerebellum were 6.1 ± 3.4, 3.7 ± 2.2 and 1.33 ± 0.38, respectively, showing binding selectivity of metabolite [¹¹C]1 to striata. Conclusion Radiometabolites [¹¹C]1 and [¹¹C]2 were characterized as the 4-hydroxymethyl and 4-carboxyl analogs of [¹¹C]PE2I, respectively. The presence of the pharmacologically active [¹¹C]1 and the inactive [¹¹C]2 is a serious impediment to successful biomathematical analysis.     

PET studies with l-[1-11C]tyrosine,l-[methyl-11C]methionine and 18F-fluorodeoxyglucose in prolactinomas in relation to bromocryptine treatment

Aspects of metabolism in prolactinomas were investigated by positron emission tomography using l-[1-¹¹C]tyrosine, l-[methyl-¹¹C]methionine and ¹⁸F-fluorodeoxyglucose (¹⁸FDG). Using l-[1-¹¹C]tyrosine, four patients were monitored prior to and 18 h after an injection of 50 mg bromocryptine. At 18 h after bromocryptine intervention, l-[1-¹¹C]tyrosine uptake into tumour was reduced with 28% (P<0.07). A correlation analysis of the bromocryptine-induced decrease in l-[1-¹¹C]tyrosine uptake and the reduction of serum prolactin levels indicated that the action of bromocryptine on prolactin synthesis and prolactin release is not coupled. In the untreated situation, the four patients were investigated with ¹⁸FDG as well, but the prolactinomas could not be visualized. Three untreated patients were studied with l-[methyl-¹¹C]methionine. The tumour-imaging potential of l-[methyl-¹¹C]methionine and l-[1-¹¹C]tyrosine appeared to be nearly equivalent for prolactinomas. Unlike prolactinoma tissue, the salivary glands showed a pronounced preference for l-[1-¹¹C]tyrosine as compared to l-[methyl-¹¹C]methionine. l-[1-¹¹C]tyrosine is a valuable tool to obtain information on the metabolism and treatment of prolactinomas.     

Development and evaluation of muscarinic cholinergic receptor ligands n-[c]ethyl-4-piperidyl benzilate and n-[c]propyl-4-piperidyl benzilate: a pet study in comparison with n-[c]methyl-4-piperidyl benzilate in the conscious monkey brain

The muscarinic cholinergic receptor ligands N-[¹¹C]ethyl-4-piperidyl benzilate (4-EPB) and N-[¹¹C]propyl-4-piperidyl benzilate (4-PPB) were developed and evaluated in comparison with N-[¹¹C]methyl-4-piperidyl benzilate (4-MPB) in the conscious monkey brain using positron emission tomography (PET). Time-activity curves of [¹¹C]4-EPB, unlike [¹¹C]4-MPB, showed peaks within 91 min in regions rich in muscarinic receptors. [¹¹C]4-PPB showed no specific binding even in the regions rich in these receptors. These observation demonstrated that increases in [¹¹C]alkyl chain length could alter the kinetic properties of receptor ligands for PET.     

Preclinical and the first clinical studies on [11C]CHIBA-1001 for mapping α7 nicotinic receptors by positron emission tomography

Objective  4-[¹¹C]methylphenyl 2,5-diazabicyclo[3.2.2]nonane-2-carboxylate ([¹¹C]CHIBA-1001), a 4-methyl-substituted derivative of the selective α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonist 4-bromophenyl 1,4 diazabicyclo[3.2.2]nonane-4-carboxylate (SSR180711), is a potential radioligand for mapping α7 nAChRs in the brain by positron emission tomography (PET). In this study, we performed preclinical and first clinical PET studies using [¹¹C]CHIBA-1001 for imaging α7 nAChRs in the human brain. Methods  [¹¹C]CHIBA-1001 was synthesized by methylation of the tributylstannyl precursor with [¹¹C]CH₃I in a palladium-promoted Stille cross-coupling reaction. The radiation absorbed-dose of [¹¹C]CHIBA-1001 in humans was calculated from distribution data in mice. The acute toxicity of CHIBA-1001 at a dose of 3.20 mg/kg body weight, which is more than 41,000-fold the clinical equivalent dose of [¹¹C]CHIBA-1001, was evaluated. The mutagenicity of CHIBA-1001 was studied by a reverse mutation test in Salmonella typhimurium (Ames test). Metabolite analysis in the mouse brain was carried out by high-performance liquid chromatography. The first clinical PET imaging of α7 nAChRs with [¹¹C]CHIBA-1001 in a normal volunteer was also performed. Results  A suitable preparation method for [¹¹C]CHIBA-1001 injection was established. The radiation absorbed-dose by [¹¹C]CHIBA-1001 in humans was low enough for clinical use, and no acute toxicity or mutagenicity of CHIBA-1001 was found. Most radioactivity in the mouse brain was detected as an unchanged form, although peripherally [¹¹C]CHIBA-1001 was degraded. We successfully performed brain imaging by PET with [¹¹C]CHIBA-1001 in a normal volunteer. A 90-min dynamic scan showed a rapid accumulation and gradual washout of radioactivity in the brain. The highest distribution volume of [¹¹C]CHIBA-1001 was found in the thalamus; however, regional differences in brain radioactivity were small. Peripherally, [¹¹C]CHIBA-1001 was stable in humans: >80% of the radioactivity in plasma was detected as the unchanged form for 60 min. Conclusions  These results demonstrate that [¹¹C]CHIBA-1001 is a suitable radioligand to use in clinical trials for imaging α7 nAChRs in the human brain, providing acceptable dosimetry and pharmacological safety at the dose required for adequate PET imaging.     

Preclinical studies on [11C]MPDX for mapping adenosine A1 receptors by positron emission tomography

In previous in vivo studies with mice, rats and cats, we have demonstrated that [11C]MPDX ([1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a potential radioligand for mapping adenosine A1 receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. The radiation absorbed-dose by [11C]MPDX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly visualized by PET with [11C]MPDX. We have concluded that [11C]MPDX is suitable for mapping adenosine A1 receptors in the human brain by PET.     

Imaging of adenosine A<Subscript>1</Subscript> receptors in the human brain by positron emission tomography with [<Superscript>11</Superscript>C]MPDX

We report the first clinical PET study using [1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine ([11C]MPDX) for imaging adenosine A1 receptors in the human brain. The binding of [11C]MPDX evaluated quantitatively as the distribution volume by a graphical analysis was high in the striatum and thalamus, and low in the cerebellum. The distribution pattern of [11C]MPDX was coincident with that of adenosine A1 receptors in vitro reported previously, and was different from those of blood flow and [18F]FDG. The [11C]MPDX PET has the potential for mapping adenosine A1 receptors in the human brain.     

Determination of 5-hydroxy-l-[β-C]tryptophan and its in vivo-formed radiolabeled metabolites in brain tissue using high performance liquid chromatography: A study supporting radiotracer kinetics obtained with positron emission tomography

A high performance liquid chromatographic system was developed for separation of ¹¹C-labeled 5-hydroxy- -tryptophan ([¹¹C]HTP) and in vivo formed radiolabeled metabolites in rat brain tissue. Analysis of brain homogenate revealed that the main part of the radioactivity was associated with ¹¹C-labeled 5-hydroxyindole-3-acetic acid after intravenous injection of [¹¹C]HTP to the rat. The serotonin synthesis rate in the brain was calculated and closely correlated to the serotonin synthesis rate in monkey and human measured using positron emission tomography.     

Carbon-11 pb-12: an attempt to visualize the dopamine d4 receptor in the primate brain with positron emission tomography

The dopamine D₄ receptor (D₄R) is expressed in low density in various extrastriatal brain regions. This receptor subtype is discussed in relation to the pathophysiology and treatment of schizophrenia but no selective positron emission tomography (PET) ligand is available to date to study the distribution in vivo. The arylpiperazine derivative N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (PB-12) is a novel, high-affinity ( K_i=0.040 nM) and selective D₄R ligand. We radiolabeled PB-12 with carbon-11 (t_1/2 20.4 min) by O-methylation of the corresponding desmethyl analogue N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-hydroxybenzamide (LM-190) with [¹¹C]methyl triflate. Derivative LM-190 was prepared by condensing 3-hydroxybenzoic acid with the appropriate amine. For the radiolabeling, the incorporation yield was >90% and the total synthesis time including high performance liquid chromatography (HPLC) purification was about 35 min. The specific radioactivity of [¹¹C]PB-12 at time of injection was 67–118 GBq·μmol⁻¹. PET studies in a cynomolgus monkey showed a high uptake and widespread distribution of radioactivity in the brain, including the neocortex and thalamus. About 40% of total radioactivity in plasma represented unchanged radioligand at 60 min after injection as determined by HPLC. Pretreatment with the D₄R ligand 3-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-1H-pyrollo[2,3-b]pyridine (L-745,870) prior to radioligand injection failed to demonstrate receptor-specific binding in the monkey brain. Furthermore, the brain radioactivity distribution was left unaffected by pretreating with unlabeled PB-12. This failure to detect a D₄R-specific signal may be related to a very low density of the D₄R in primate brain, insufficient binding affinity of the radioligand, and a high background of nonspecific binding. It can be concluded from these findings that [¹¹C]PB-12 is not suitable to visualize the D₄R in the primate brain with PET.     

Effects of smoking on the lung accumulation of [<Superscript>11</Superscript>C]McN5652

Objective The lung is one of the key organs for determining the distribution of drugs in the human body. Various factors influence the accumulation of drugs. In this study, we investigated the effects of smoking on drug distribution to the lung using radiolabeled drugs. Methods We measured the lung uptake of [¹¹C](+)McN5652, a radioligand for serotonin transporter (5-HTT), and inactive enantiomer [¹¹C](−)McN5652 in 19 healthy men (12 nonsmokers and 7 smokers) using positron emission tomography. Pretreatment study was performed by the administration of clomipramine (50 mg), a potent 5-HTT inhibitor. Results The mean lung uptake of [¹¹C](+)McN5652 and [¹¹C](−)McN5652 was significantly higher in smokers than in nonsmokers. The lung uptake of [¹¹C](+)McN5652 decreased after pretreatment with clomipramine, whereas that of [¹¹C](−)McN5652 was not affected by clomipramine. Conclusions Lung uptake of [¹¹C](−)McN5652 was influenced by smoking, possibly because the probable nonspecific binding accumulation was changed as [¹¹C](−)McN5652 was reported to have negligible affinity to 5-HTT. Smoking might be one of the important factors when distribution of radioligands is considered.     

Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

Purpose

Positron emission tomography (PET) imaging of serotonin 2A (5-HT_2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT_2A receptors in their high-affinity state. We have previously validated [¹¹C]Cimbi-5 and found that it is a 5-HT_2A receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [¹¹C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT_2A receptor agonist PET tracers in the pig brain.

Methods

Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90?min in a high-resolution research tomography scanner. To evaluate 5-HT_2A receptor binding, cortical nondisplaceable binding potentials (BP_ND) were calculated using the simplified reference tissue model with the cerebellum as a reference region.

Results

After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT_2A receptor distribution. The largest target-to-background binding ratio was found for [¹¹C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [¹¹C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT_2A receptor selectivity in vivo. [¹¹C]Cimbi-82 and [¹¹C]Cimbi-21 showed lower cortical BP_ND, while [¹¹C]Cimbi-27, [¹¹C]Cimbi-29, [¹¹C]Cimbi-31 and [¹¹C]Cimbi-88 gave rise to cortical BP_ND similar to that of [¹¹C]Cimbi-5.

Conclusion

[¹¹C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT_2A receptor agonist binding in the living human brain with PET.     

Synthesis and in vivo evaluation of [C]methyl-Ro 64-6198 as an ORL1 receptor imaging agent

(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-3-N-[¹¹C]methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one ([¹¹C]methyl-Ro 64-6198), a N-methylated analog of Ro 64-6198, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain nociceptin/orphanin FQ receptors (ORL1 receptors) by positron emission tomography. A racemate of methyl-Ro 64-6198, Ro 66-7931, showed a high affinity and selectivity for the ORL1 receptor in vitro. An in vivo distribution study in mice demonstrated moderate brain uptake, however, only slight difference was observed among brain regions. Furthermore, pretreating with nociceptin or Ro 66-7931 did not affect the accumulation. Therefore, despite its high affinity, [¹¹C]methyl-Ro 64-6198 does not appear to be a suitable tracer for in vivo ORL1 receptor imaging studies.     

Synthesis of a 11C-labeled novel,quinuclidine based ligand for the 5-HT3 receptor

L-683,877, a high affinity, 5-HT₃ selective receptor ligand has been labeled with ¹¹C for use in PET studies to measure regional brain kinetics of L-683,877 and to determine if [¹¹C]L-683,877 can be used for serotonin 5-HT₃ receptor imaging. [¹¹C]L-683,877 was prepared by reacting [¹¹C]methyl iodide with the desmethyl, borane-protected precursor, L-686,472, in DMF in the presence of tetrabutyl ammonium hydroxide. The average specific activity of [¹¹C]L-683,877 was 2700 Ci/mmol and the average radiochemical yield (decay uncorrected) was 20% at the end of synthesis (22 min from EOB).     

Carbon 11 labeling of the psychoactive drug O-methyl-bufotenine and its distribution in the animal organism

A methylated derivative of serotonin, O-methyl-bufotenine has been labeled with ¹¹C on the two methyl groups of the amine function. In order to avoid the cyclization which occurs during the Eschweiler-Clarke synthesis, we adopted a milder methylation procedure, based on Borch's method using [¹¹C]formaldehyde and sodium cyanoborohydride. Several tens of millicuries of injectable product could be obtained in 50 min in a perfectly pure state and having a specific radioactivity of 50 to 100mCi/mol.The distribution study of O-methyl-bufotenine in the mouse and rabbit showed an accumulation of significant quantities of the compound in the brain, kidneys, lungs and liver. The study of the rapid kinetics of this hallucinogenic molecule is compatible with labeling by ¹¹C, having a period of 20 min. The use of O-methyl-[¹¹C]bufotenine to detect serotonin receptors in vivo in mental diseases, is considered.with the technical assistance of Jacqueline Sastre     

Adenosine A1 receptors using 8-dicyclopropylmethyl-1-[11C]methyl-3-propylxanthine PET in Alzheimer’s disease

Objective  Adenosine is an endogenous modulator of synaptic functions in the central nervous system. The effects of adenosine are mediated by at least four adenosine receptor subtypes. Decreased density of adenosine A1 receptors, which is a major subtype adenosine receptor in the hippocampus, has been reported in vitro in Alzheimer’s disease. We evaluated adenosine A1 receptor in the brain of elderly normal subjects and patients with Alzheimer’s disease (n = 8 and 6, respectively), using positron emission tomography (PET) and 8- dicyclopropylmethyl-1-[¹¹C]methyl-3-propylxanthine ([¹¹C]MPDX). Methods  A 60-min PET scan with [¹¹C]MPDX was performed. The patients with Alzheimer’s disease also underwent PET with [¹⁸F]fluorodeoxyglucose (FDG). The binding potential of [11C]MPDX was quantitatively calculated in the regions of interest (ROIs) placed on the frontal, medial frontal, temporal, medial temporal, parietal, and occipital cortices, striatum, thalamus, cerebellum, and pons. Statistical parametric mapping (SPM2) was used for analysis of [¹¹C]MPDX and FDG-PET. Results  In the ROI-based analysis, the binding potential of [¹¹C]MPDX in patients with Alzheimer’s disease was significantly lower in the temporal and medial temporal cortices and thalamus than that in elderly normal subjects (P = 0.038, 0.028, and 0.039, respectively). SPM analysis also showed significant decreased binding potential in the temporal and medial temporal cortices and thalamus in patients with Alzheimer’s disease. FDG uptake was significantly decreased in the temporoparietal cortex and posterior cingulate gyrus. Conclusions  Decreased binding of [¹¹C]MPDX in patients with Alzheimer’s disease was detected in temporal and medial temporal cortices and thalamus. This pattern possibly differed from the hypometabolism pattern of FDG. [¹¹C]MPDX PET is valuable for the detection of degeneration in the temporal and medial temporal cortices and corticothalamic transmission, and may provide a different diagnostic tool from FDG-PET in brain disorders such as Alzheimer’s disease.     

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

The serotonin 5-HT_1B 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 positron emission tomography (PET) tracer for imaging the 5-HT_1B 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 scanner with a bolus/infusion paradigm. Binding potential (BP_ND) 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-HT_1B receptors. Infusion of tracer at different specific activities (by adding various amount of unlabeled P943) reduced BP_ND values in a dose-dependent manner, demonstrating the saturability of the tracer binding. Blocking studies with GR127935 (2 mg/kg iv), a selective 5-HT_1B/5-HT_1D antagonist, resulted in reduction of BP_ND 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 5-HT_1B receptors, suggesting its suitability as a PET radiotracer for in vivo evaluations of the 5-HT_1B receptor system in humans.