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An agonist PET tracer is of key interest for the imaging of the 5-HT2A receptor, as exemplified by the previously reported success of [11C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an 18F-labelled agonist 5-HT2A receptor (5-HT2AR) tracer is highly sought after. Herein, we report a 2-step, 1-pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5-HT2AR. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs. PET images partially conformed to the expected brain distribution of the 5-HT2AR; a notable exception however being significant uptake in the striatum and thalamus. Additionally, a within-scan displacement challenge with a 5-HT2AR antagonist was unsuccessful, indicating that the tracers cannot be considered optimal for neuroimaging of the 5-HT2AR. [ABSTRACT FROM AUTHOR]

Purpose: [C]Cimbi-36 was recently developed as an agonist radioligand for brain imaging of serotonin 2A receptors (5-HT) with positron emission tomography (PET). This may be used to quantify the high-affinity state of 5-HT receptors and may have the potential to quantify changes in cerebral 5-HT levels in vivo. We here investigated safety aspects related to clinical use of [C]Cimbi-36, including radiation dosimetry and in vivo pharmacology. Procedures: [C]Cimbi-36 was injected in rats or pigs, and radiation dosimetry was examined by ex vivo dissection or with PET scanning, respectively. Based on animal data, the Organ Level INternal Dose Assessment software was used to estimate extrapolated human dosimetry for [C]Cimbi-36. The 5-HT receptor agonist actions of [C]Cimbi-36 in vivo pharmacological effects in mice elicited by increasing doses of Cimbi-36 were assessed with the head-twitch response (HTR). Results: The effective dose as extrapolated from both rat and pig data was low, 7.67 and 4.88 μSv/MBq, respectively. In addition, the estimated absorbed radiation dose to human target organs did not exceed safety levels. Administration of 0.5 mg/kg Cimbi-36 leads to significant HTR compared to saline, whereas 0.05 mg/kg Cimbi-36 (doses much larger than those given in conjunction with a PET scan) did not elicit a significant HTR. Conclusions: Administration of tracer doses of [C]Cimbi-36 does not seem to be associated with unusual radiation burden or adverse clinical effects. [ABSTRACT FROM AUTHOR]

ABSTRACT Imaging the cerebral serotonin 2A (5-HT2A) receptors with positron emission tomography (PET) has been carried out in humans with [11C]MDL 100907 and [18F]altanserin. Recently, the MDL 100907 analogue [18F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we present a direct comparison of [18F]altanserin and [18F]MH.MZ. 5-HT2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [3H]MDL 100907, [18F]MH.MZ, and [18F]altanserin. [18F]MH.MZ and [18F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue-compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [18F]MH.MZ and [18F]altanserin. Significant 5-HT2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [18F]MH.MZ and [18F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT2A receptors in the pig brain. In the HPLC analysis of pig plasma, [18F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [18F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [18F]MH.MZ in high-binding regions in vivo, we suggest that [18F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [18F]altanserin is a suitable tracer for high-binding regions. Synapse, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Cerebral α1-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of α1-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs targeting the α1-adrenoceptors. However, so far no suitable PET radioligand has been developed for brain imaging of α1-adrenoceptors. Here, we report the synthesis of both enantiomers of the desmethyl precursors of the high affinity α1-adrenoceptor ligand Lu AE43936 ( 1 ). The two enantiomers of 1 were subsequently [11C] radiolabelled and evaluated for brain uptake and binding by PET imaging in Danish Landrace pigs. (S)-[11C]- 1 and (R)-[11C]- 1 showed very limited brain uptake. Pre-treatment with cyclosporine A (CsA) resulted in a large increase in brain uptake, indicating that (R)-[11C]- 1 is a substrate for active efflux-transporters. This was confirmed in Madin Darby canine kidney (MDCK) cells overexpressing permeability glycoprotein (Pgp). In conclusion, the limited brain uptake of both (S)-[11C]- 1 and (R)-[11C]- 1 in the pig brain necessitates the search for alternative radioligands for in vivo PET brain imaging of α1-adrenoceptors. [Copyright &y& Elsevier]

The main objective of this study was to determine the sensitivity of [11C]CUMI-101 to citalopram challenge aiming at increasing extracellular 5-HT. CUMI-101 has agonistic properties in human embryonic kidney 293 cells transfected with human recombinant 5-HT1A receptors (Hendry et al. [2011] Nucl Med Biol 38:273-277; Kumar et al. [2006] J Med Chem 49:125-134) and has previously been demonstrated to be sensitive to bolus citalopram in monkeys (Milak et al. [2011] J Cereb Blood Flow Metab 31:243-249). We studied six healthy individuals. Two PET-scans were performed on the same day in each individual before and after constant infusion of citalopram (0.15 mg/kg). The imaging data were analyzed using two tissue compartment kinetic modeling with metabolite corrected arterial input and Simplified Reference Tissue Modeling using cerebellum as a reference region. There was no significant difference in regional distribution volume or non-displaceable binding potential values before and after citalopram infusion. The mean receptor occupancy was 0.03 (range −0.14 to 0.17). Our data imply that [11C]CUMI-101 binding is not sensitive to citalopram infusion in humans. Synapse, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: 2-(2′,6′-Dimethoxy-[1,1′-biphenyl]-3-yl)-N,N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT7) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [11C]2-(2′,6′-dimethoxy-[1,1′-biphenyl]-3-yl)-N,N-dimethylethanamine ([11C]Cimbi-806) as a radioligand for imaging brain 5-HT7 receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent 11C-labelling with [11C]methyltriflate produced [11C]Cimbi-806 in specific activities ranging from 50 to 300GBq/μmol. Following intravenous injection, brain uptake and distribution of [11C]Cimbi-806 was assessed with PET in Danish Landrace pigs. The time–activity curves revealed high brain uptake in thalamic and striatal regions (SUV ∼2.5) and kinetic modeling resulted in distribution volumes (V T) ranging from 6mL/cm3 in the cerebellum to 12mL/cm3 in the thalamus. Pretreatment with the 5-HT7 receptor antagonist SB-269970 did not result in any significant changes in [11C]Cimbi-806 binding in any of the analyzed regions. Despite the high brain uptake and relevant distribution pattern, the absence of appropriate in vivo blocking with a 5-HT7 receptor selective compounds renders the conclusion that [11C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT7 receptor in vivo. [Copyright &y& Elsevier]

Introduction The serotonin 2A receptor (5-HT 2A R) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT 2A R PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT 2A R agonist PET tracer, [ 11 C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an 18 F-labeled 5-HT 2A R agonist PET-ligand. Methods and results Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT 2A agonists. 18 F-labeling of the appropriate precursors was performed using [ 18 F]FETos, typically yielding 0.2–2.0 GBq and specific activities of 40–120 GBq/μmol. PET studies in Danish landrace pigs revealed that [ 18 F] 1 displayed brain uptake in 5-HT 2A R rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT 2A R selective antagonist. [ 18 F] 2 and [ 18 F] 3 showed very low brain uptake. Conclusion None of the investigated 18 F-labeled Cimbi-36 derivatives [ 18 F] 1 , [ 18 F] 2 and [ 18 F] 3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT 2A R. Although for [ 18 F] 1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT 2A R antagonist. [ABSTRACT FROM AUTHOR]

Abstract: In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [11C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [11C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands. [Copyright &y& Elsevier]

Abstract: Here we describe the design, synthesis, and pharmacological evaluation of a set of compounds structurally related to the high affinity serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT1A and adrenergic α1 receptors. The synthesized compounds have chemical features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabeled on the methoxy group with carbon-11. Positron emission tomography (PET) analysis revealed that [11C]-23a and [11C]-26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests. [Copyright &y& Elsevier]