Development of [Carbonyl-11C]AZ13198083, a Novel Histamine Type

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Development of [carbonyl-11C]AZ13198083, a novel histamine type-3 receptor radioligand with favorable kinetics Kenneth Dahl, Ryuji Nakao, Nahid Amini, Mohammad Mahdi Moein, Sjoerd J Finnema, Jonas Malmquist, Katarina Varnas, and Magnus Schou ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00493 • Publication Date (Web): 23 Jan 2018 Downloaded from http://pubs.acs.org on January 24, 2018

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ACS Chemical Neuroscience

Development of [carbonyl-11C]AZ13198083, a novel histamine typetype-3 receptor radioligand with favorable kinetics Kenneth Dahl,† Ryuji Nakao,† Nahid Amini,† Mohammad Mahdi Moein,† Sjoerd Finnema,† Jonas Malmquist‡, Katarina Varnäs,† and Magnus Schou*, †, ‡ †Department

of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-171 76 Stockholm, Sweden ‡PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, S-171 76 Stockholm, Sweden. KEYWORDS: PET imaging, radioligand, receptor, histamine, carbon-11, carbonylation

ABSTRACT: The histamine subtype-3 receptor (H3R) is implicated in a range of central nervous system disorders and several radioligands have been developed for H3R positron emission tomography imaging. However, a limitation of currently used PET radioligands for H3R is the slow binding kinetics in high density brain regions. To address this, we herein report the development of three novel candidate H3 R radioligands, namely, [carbonyl-11C]AZ13153556 ([carbonyl-11C]4), [carbonyl11 11 11 11 C]AZD5213([carbonyl- C]5), and [carbonyl- C]AZ13198083 ([carbonyl- C]6), and their subsequent preclinical evaluation in non-human primates (NHP). Radioligands [carbonyl-11C]4-6 were produced and isolated in high radioactivity (>1000 MBq), radiochemical purity (> 99%), and moderate molar activity (19-28 GBq/µmol at time of injection) using a palladium-mediated 11Caminocarbonylation protocol. All three radioligands showed high brain permeability as well as a regional brain radioactivity distribution in accordance with H3R expression (striatum > cortex > cerebellum). [Carbonyl-11C]6 displayed the most favorable in vivo kinetics and brain uptake, with an early peak in the striatal time-activity curve followed by a progressive washout from the brain. The specificity and on-target kinetics of [carbonyl-11C]6 were next investigated in pretreatment and displacement studies. After pretreatment or displacement with 5 (0.1 mg/kg), a uniformly low distribution of radioactivity across the NHP brain was observed. Collectively, this work demonstrates that [carbonyl-11C]6 is a promising candidate for H3R imaging in human subjects.

The histamine type-3 receptor (H3R) is widely expressed in the central nervous system (CNS) where it plays an important role in regulating the release of the neurotransmitters histamine, dopamine and noradrenaline. The highest H3R densities in brain are found in regions involved in cognitive processes (e.g. cerebral cortex and basal ganglia). H3Rs have been implicated in a range of disorders including Alzheimer’s disease, schizophrenia, obesity and diabetes.1-5 Positron emission tomography (PET) is a sensitive noninvasive imaging technique. The PET technology relies upon the intravenous administration of a radiolabeled imaging agent (radioligand) that serves as a molecular probe to investigate biological processes in vivo.6-9 A number of H3R PET radioligands have been reported,10-20 but only a few have shown promise in vivo. Of these, three have so far been translated for human use, namely, [11C]MK8278 ([11C]1)16, [11C]GSK189254 ([11C]2)13, 19, and [11C]TASP457 ([11C]3)20 (Figure 1, top). A common feature with these radioligands is the slow binding kinetics in high density brain regions, which in turn, leads to high variance in estimates of binding parameters. Figure 1. Top: PET radioligands translated for in human imaging of the H3R. Bottom: Structures of our previous and current efforts to H3R radioligand development.

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Table 1. Radiosynthesis of three novel histamine subtype-3 receptor PET radioligands ([carbonyl-11C]4-6) using Pd-mediated 11Ccarbonylative coupling of a bromoarene with primary amines.[a]

Radioligand ([carbonyl-11C]4-6) [carbonyl-11C]4 [carbonyl-11C]5 [carbonyl-11C]6

Amine (8a-c)

8a, NH2CH3 8b, NH3 8c, NH2C2H5

Radiochemical yield (%)b 80 96 95

Radiochemical purity (%)c >99 >99 >99

Synthesis (min)d

time

41 32 38

Molar Activity at TOI (GBq/µmol)e 19 28 23

[a] Conditions: Bromo-precursor (7, 20 µmol), amine (8a-c, 200 µmol), Pd2[cinnamyl-π]Cl2 (14 µmol), xantphos (14 µmol), anhydrous THF (Tetrahydrofuran, 500 µL), 100ᵒC, 5 min. [b] Decay-corrected and non-isolated radiochemical yield relative to the amount of [11C]CO delivered to the reaction vessel. [c] Radiochemical purity of isolated products measured by analytical highperformance liquid chromatography. [d] The overall synthesis time, including 11C-labeling, purification, formulation and sterile filtration. [e] Molar Activity of isolated products measured by analytical high-performance liquid chromatography and calculated at TOI (time-of-injection).

Figure 2. Time-activity curves for the concentration of radioactivity in various monkey brain regions as a function of time following intravenous injection of [carbonyl-11C]4 (left), [carbonyl-11C]5 (middle), [carbonyl-11C]6 (right) at baseline. STR, striatum; PFC, prefrontal cortex; OC, occipital cortex; CER, cerebellum.

We previously reported the development of [methyl11 C]AZ13153556 ([methyl-11C]4),21 a H3R selective PET radioligand that showed good imaging properties in vivo, including high brain uptake, reversible binding and negligible nonspecific binding in non-human primate (NHP) brain. However, in common with [11C]1-3, [methyl-11C]4 also displayed relatively slow binding kinetics in regions with high H3R density. Herein, we report the radiosyntheses and preclinical evaluation of two novel H3R PET radioligands, [carbonyl11 C]AZD5213 ([carbonyl-11C]5) and [carbonyl11 C]AZ13198083 ([carbonyl-11C]6), as well as, [carbonyl11 C]4 (Figure 1, bottom), in order to explore the impact of amide substituents on brain kinetics in vivo.

RESULTS AND DISCUSSION Radiochemistry. 11C-labeled carbon monoxide ([11C]CO) has been increasingly recognized as an important 11C-labeling agent for radiopharmaceutical research and production.22-26 No-carrier-added (nca) [11C]CO is commonly obtained from cyclotron produced [11C]carbon dioxide ([11C]CO2) by metalmediated on-line reduction27-29, and can be employed in many metal-mediated carbonylation reactions, giving rise to a wide library of radiolabeled compounds. Various ketones, amides, esters, carboxylic acids, ureas and carbamates are examples of functional groups accessible via metal-mediated 11Ccarbonylation reactions.22-24 As neither 5 or 6 have a terminal methyl group present, the standard radiomethylation protocol


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ACS Chemical Neuroscience was abandoned for a high throughput labeling strategy based on [11C]CO (Table 1). Radioligands [carbonyl-11C]4-6 were efficiently prepared by [11C]aminocarbonylation of the corresponding aryl bromide precursor.30-31 Reaction conditions and production data are shown in Table 1. The reaction was conducted using 7 as substrate, [11C]CO as the 11C-source, an amine (8a-c), and Pd2(π-cinnamyl)Cl2-xantphos as catalyst with anhydrous tetrahydrofuran (THF) as solvent. In this study, nca [11C]CO (radiochemical yield (RCY) ~ 70%) was produced by on-line reduction of in-target produced [11C]CO2 over heated (850ᵒC) molybdenum.27 The [11C]CO was next reacted (100ᵒC for 5 min) with the precursor-solution in a steel reaction chamber (µ-autoclave, V = 250 µL) submerged in an oil bath.32 When the 11C-carbonylative step was completed, the mixture was automatically eluted into a receiving vial for further purification. Radioligands [carbonyl-11C]4-6 were produced in radioactivities >1 GBq (27 mCi, isolated, formulated and sterile filtered) and >99% radiochemical purity (RCP) using the present conditions. The overall synthesis time was 32-41 min and the molar activity (Am) 19-28 GBq/µmol (513-757 Ci/mmol) at the time-of-injection. The obtained Am during this study was 10-fold lower compared to our previous study with [methyl-11C]4.21 However, it is on a similar level as other radioligands prepared from [11C]CO in our laboratory.29 Preclinical PET imaging. With the radioligands in hand, we conducted dynamic PET imaging studies in female cynomolgus monkeys. The aim of the initial NHP studies was to evaluate the suitability of [carbonyl-11C]4-6 as PET radioligands with regards to; (i) blood brain barrier (BBB) permeability, (ii) regional brain distribution, and (iii) brain kinetics. To facilitate a direct comparison, each radioligand ([carbonyl11 C]4-6) was injected intravenously in the same monkey on the same experimental day. Following a 123 min emission measurement, PET images were reconstructed and region of interests (ROIs) were delineated based on magnetic resonance (MR) images. Time-radioactivity curves (TACs) for the regional brain distribution of [carbonyl-11C]4-6 were next generated (Figure 2). All three radioligands rapidly crossed the BBB and showed a regional brain distribution consistent with H3R expression.33-34 The regional uptake was most prominent in H3R-rich regions, such as striatum, while moderate in the cortex and significantly lower in cerebellum (Figure 2). Importantly, we observed a significant difference in both brain uptake and kinetics between the three radioligands. For example, a peak in the striatal TAC was not observed during the entire PET measurement with [carbonyl-11C]5 (Figure 2, middle), whereas TAC peaks were obtained early with both [carbonyl-11C]4 and [carbonyl-11C]6. The subsequent washout from striatum was on the other hand considerably more rapid with [carbonyl-11C]6 than with [carbonyl-11C]4 (Figure 2). The faster brain kinetics observed with [carbonyl-11C]6 could, at least in part, be explained by its 4-fold lower affinity for the H3R in vitro (4, IC50 = 6.4 nM; 6, IC50 = 24 nM). During the PET measurements, radiolabeled metabolites in plasma were analyzed using radio-HPLC (see supporting information for further information). Interestingly, [carbonyl-11C]6 was more rapidly metabolized compared to [carbonyl-11C]4. This likely also contributes to the accelerated wash-out of [carbonyl-11C]6 from brain by shifting the equilibrium between radioligand concentration in brain and plasma towards plasma. It is noteworthy that [carbonyl-11C]4 displayed a slightly better

in vivo binding kinetics in comparison to our previously reported 11C-methylated analogue, [methyl-11C]4.21 One possible explanation for this may be the lower molar activity obtained in the current study, (i.e. a mass effect). Such mass effects are not uncommon for high affinity PET radioligands and was indeed reported for H3R imaging in human subjects with [11C]GSK189254, where a dose lower than 0.003 µg/kg of body weight was recommended to achieve less than 5% occupancy induced by the carrier.19 Based on its favorable kinetics and regional brain distribution, [carbonyl-11C]6 was chosen for further evaluation. First a pretreatment study was performed, in which the selective H3R antagonist 5 was infused at a dose (0.1 mg/kg) known to occupy >95% of H3R in human brain.35 TACs for the regional brain distribution of [carbonyl-11C]6 were generated at baseline (Figure 3, top) and at pretreatment conditions (Figure 3, bottom). Gratifyingly, pre-treatment with 5 almost completely inhibited the specific binding of [carbonyl-11C]6 in the examined H3R rich regions, leading to a uniformly low distribution of radioactivity in the NHP brain. The strong effect of 5 on the regional distribution of [carbonyl-11C]6 supports the view that binding of this radioligand is predominantly specific to the H3R. Summed PET-MR images (3-123 min) after intravenous administration of [carbonyl-11C]6 in monkey brain at baseline (Figure 4, top) and pre-treatment conditions (Figure 4, bottom) are shown in Figure 4. Finally, the binding of [carbonyl-11C]6 was characterized by a displacement study in which 5 was administered 60 minutes after [carbonyl-11C]6. TACs of [carbonyl-11C]6 were generated at baseline (Figure 5, top) and after displacement (Figure 5, bottom). Following injection of 5, there was a rapid reduction of [carbonyl-11C]6 binding in the brain, demonstrating the rapid reversibility of [carbonyl-11C]6 binding to the H3R in vivo.



CONCLUSION [Carbonyl-11C]6 fulfils several criteria for successful neuroreceptor imaging in vivo in non-human primates. These include: (i) high BBB permeability (ii) high specific binding and (iii) reversible binding to the H3R. The favorable kinetics of [carbonyl-11C]6 in brain may offer an improved sensitivity towards changes in endogenous histamine concentrations.

METHODS Radiochemistry. HPLC solvents were obtained from Fisher (Sweden). Unless otherwise stated, all other reagents and solvents were obtained from Sigma-Aldrich (Sweden) and used without further purification. Bromo-precursor (7) as well as the standard compounds (4-6) were supplied by AstraZeneca. General procedure for radiolabeling with [11C]CO. No-carrieradded [11C]CO2 was produced using 16.5 MeV protons in the 14 N(p,α)11C nuclear reaction on a mixture of nitrogen and oxygen gas (0.5% oxygen). [11C]CO2 was converted to [11C]CO and subsequently reacted with the coupling reagents (Bromoarene precursor (7), Pd2(π-cinnamyl)Cl2, xantphos and amine (8a-c) in anhydrous THF using a high-pressure micro-autoclave system as previously described elsewhere.28 Purification and formulation was performed using a computer controlled automated system (DMAutomation, Sweden). Semi-preparative HPLC was performed using a reversed-phase C-18 column (µBondapak, 10 µm, 10 x 300 mm, Waters) eluted with MeCN- HCO2NH4 (50 mM) 25: 75 v/v at 6 mL/min. The column outlet was connected with an absorbance detector (λ = 254 nm) in a series with radiation detector. The purified products were further purified using a solid phase extraction (SepPak, C18 plus short, Waters) and finally formulated using 5% ethanol in PBS (phosphate buffered saline, pH 7.4). Analytical chromatograms and methods for [carbonyl11 C]4-6 can be found in the supporting information.

Figure 3. Time-activity curves for the concentration of radioactivity in various brain regions as a function of time (0-123 min) following the intravenous injection of [carbonyl-11C]6 at baseline (top) and pre-treatment conditions with 5 (bottom). STR, striatum; PFC, prefrontal cortex; OC, occipital cortex; CER, cerebellum.

PET imaging in non-human primates. The study was approved by the Animal Ethics Committee of the Swedish Animal Welfare Agency (Dnr 145/08, 399/08 and 386/09) and was performed according to the “Guidelines for planning, conducting and documenting experimental research” (Dnr 4820/06-600) at the Karolinska Institutet, the Guide for the Care and Use of Laboratory Animals” the AstraZeneca bioethics policy and the EU Directive 2010/63/EU. Seven PET experiments were performed in three different experiment sessions. Session 1: Baseline PET measurements with 152157 MBq of [carbonyl-11C]4-6 in cynomolgus monkey 1 (6.9 kg). Session 2: Baseline PET measurements with 155 MBq of [carbonyl-11C]6 in cynomolgus monkey 2 (6.2 kg) followed by a pretreatment PET measurement in which AZD5213 (5, 0.1 mg/kg) was infused during 10 min starting 30 min before injection of [carbonyl-11C]6 (157 MBq). Session 3: Baseline PET measurement with 158 MBq of [carbonyl-11C]6 in cynomolgus monkey 3 (6.5 kg) followed by a displacement PET measurement in which 5 (0.1 mg/kg) was infused during 10 min starting one hour after injection of [carbonyl-11C]6 (164 MBq).

Figure 4. Representative color-coded PET-MR images showing distribution of radioactivity in cynomolgus monkey brain following the intravenous injection of [carbonyl-11C]6 at baseline (top) and pre-treatment conditions (5, 0.1 mg/kg; bottom). The images represent a summary of radioactivity from 3 to 123 min after [carbonyl-11C]6 injection. Image intensity was corrected for radioactivity.

A head fixation system was used to secure a fixed position of the monkey’s head throughout the PET measurements undertaken in each experimental session. In each PET experiment, the radiotracer was formulated in sterile physiological phosphate buffer (pH 7.4) solution containing 5 % ethanol and injected as a bolus into a sural vein during 5 s with simultaneous start of PET data acquisi-


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ACS Chemical Neuroscience tion. Radioactivity in the brain was measured continuously for 123 min according to a preprogrammed series of 34 frames.

We are grateful to Arsalan Amir, Guennadi Jogolev, Gudrun Nylén, Julio Gabriel, and all other members of the PET center at Karolinska Institutet. The authors also thank Dr. Vadim BernardGauthier for linguistic review.

REFERENCES

Figure 5. Time-activity curves for the concentration of radioactivity in various brain regions as a function of time (0-123 min) following the intravenous injection of [carbonyl-11C]6 at baseline (top) and displacement conditions with 5 (bottom). The arrow indicates the start of the infusion of 5. STR, striatum; PFC, prefrontal cortex; OC, occipital cortex; CER, cerebellum.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]. Tel: +46-8-51775598

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Funding Sources The study was funded by AstraZeneca

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

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Development of [Carbonyl-11C]AZ13198083, a Novel Histamine Type

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