Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis

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Poly (ADP-ribose) polymerase in neurodegeneration: Radiosynthesis and radioligand binding in ARC-SWE tg mice. Santosh Reddy Alluri, and Patrick J Riss ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00053 • Publication Date (Web): 15 Mar 2018 Downloaded from http://pubs.acs.org on March 16, 2018

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ACS Chemical Neuroscience

Poly (ADP-ribose) polymerase in neurodegeneration: Radiosynthesis and radioligand binding in ARC-SWE tg mice Santosh R. Alluri,† Patrick J. Riss†‡ †Realomics SFI, Kjemisk Institute, Universitetet i Oslo, Sem Sæalands Vei 26, Kjemibygningen, 0371, Oslo, Norway ‡Klinik for Kirurgi og Nevrofag, Oslo Universitets Sykehus HF−Rikshospitalet, Postboks 4950 Nydalen, 0424 Oslo, Norway

KEYWORDS: PARP, Rucaparib, Autoradiography ABSTRACT: We report the synthesis, radiosynthesis and characterization of a radioligand for poly (ADP-ribose) polymerase (PARP). PARP is of central importance in cell homeostasis, neuroplasticity and neurodegeneration in the brain. A radiolabelled PARP inhibitor was developed and used for autoradiographic quantification of PARP protein concentration in wildtype and transgenic rodent brains ex vivo in high resolution. The binding of [3H]rucaparib was found to be confined to PARP-expressing domains e.g. cerebellar cortex or hippocampal regions in both models. Saturation binding experiments confirmed selective and reversible binding to a single site (Kd = 1.1±0.2 nM).

INTRODUCTION The enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is one of the 17 members of the PARP family. It is a nuclear enzyme that uses nicotinamide adenine dinucleotide (NAD+) as its substrate to catalyze poly ADP-ribosylation on acceptor proteins.1 DNA damage activates PARP-1, activated PARP-1 then adds ADP-ribose to form a polymeric, energy rich scaffold of poly-ADP-ribose) (PAR).1,2 PAR is a very critical resource in cell homeostasis and repair. For example, base excision repair (BER) and single strand break repair (SSBR) mechanisms rely on PAR for energy. The roles of PARP in disease are both ample and critical, mainly via disease mechanisms involving PAR or PARP in their primary functions. The most prominent include neuroplasticity, neuroprotection/neurodegeneration and the main repair pathways in radiation therapy.3,4,5 A PARP specific neurodegenerative mechanism, termed parthanatos, has been linked to PARP overactivation in response to DNA damage, which leads to cellular depletion of NAD+, ATP, and, finally, nuclear translocation of apoptosis inducing factor resulting in controlled cell death.6 We are interested in the role of PARP in long term memory formation/synaptic plasticity.7,8 Alterations in PARylation were shown to be implicated in changes transcription/epigenetic patterns and thereby contribute to neurodegeneration, for example in Alzheimer’s disease (AD).5,9- 10 PARylation on nuclear proteins is regarded as one of the chromatin modifiers, the latter initiate new gene expression and protein synthesis,8 and depletion of PARP signal in histochemical studies was found in AD.11 Notably, PARP inhibition was proven to be viable to neuroprotection in some animal models.12,13 Alterations in PARP activity were indicated in human postmortem sections of Alzheimer’s brains.9,10 Therefore we surmised that PARP protein concentration is associated with long-term synaptic changes including impaired synaptic plasticity, tentatively even early in the disease. However, so far no studies on functional PARP-1 protein and no radioligands suitable for the measurements in high resolution

have been described. We decided to investigate a high affinity PARP-1 inhibitor as a novel radioligand to map PARP in brain in relation to neurodegenration and brain damage. Herein, we describe the synthesis and radiosynthesis of [3H]rucaparib. A proof of principle study is conducted in a mouse model of (amyloidogenic) dementia to test if lower PARP expression is detectable on the protein level. Concentration dependent binding was determined to quantify PARP distribution using high resolution autoradiography.

RESULTS AND DISCUSSION Rucaparib (AG 014699) is a selective PARP-1 inhibitor used in clinical care. It has Ki value of 1.4 nM, which is the highest value found in the literature.14 A crystal structure of rucaparib bound to PARP-1 active site has already been published which gave us confidence to use this compound to study PARP in vivo. Very few syntheses of rucaparib 1 and its analogues e.g. 2 were reported. The key synthetic intermediate to obtain rucaparib is the tricylic indolazepine 1f (Scheme 1). Scheme 1. Rucaparib and its synthetic intermediate

Few syntheses of 1f and its analog 2f has been reported in good yield from a relatively expensive methyl 6-fluoro indole 4-carboxylate (4 steps from 2-methyl 5-fluoro benzoic acid) over 3 steps.15,16,17 We devised a synthetic strategy that could yield 1f over 4 steps from relatively cheap 6-fluoro indole 1a starting material via an intramolecular cyclization route (Scheme 2). Rucaparib analog 2 was also synthesized using this route along with 1.

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Scheme 2. Synthetic route to 1f

Scheme 3: Synthesis of key intermediates 1f and 2f

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Having 1d in hand, we proceeded further to prepare 1f. The Schmidt rearrangement (HCl, NaN3) of 1d gave the desired 1e in poor yields even using excess amount of reagents. Besides the ketones 1d and 2d were also degraded to some extent in acid media. Therefore 1d was first converted to its oxime derivative and then subjected to Beckmann rearrangement to obtain 1e (Supporting information, Scheme 2). In presence of H2SO4, the oxime derivative of 1d gave a complex mixture of products and 1e was difficult to isolate. It was assumed that H2SO4 gave both the desired and undesired products due to alkyl and aryl migration trans to nitrogen.20 Instead heating the oxime derivative of 1d with SOCl2 gave the desired 1e as the sole product in moderate 40% yield along with black tar. The formation of 1e was confirmed by the coupling between amide proton and adjacent –CH2 group protons (1H-COSY NMR). In the next step, the pivaloyl group was removed by DBU and water to give 1f and 2f in very good yields. Table 1: Attempted syntheses to improve 1d yieldx

Reagents and conditions: i. (CH3CO)2O, CH3COOH, 50°C, 48 h, 1b 50%; ii. n-BuLi, -78°C, THF, 30 min, pivaloyl chloride, 1 h, 1c 80%, 2c 82%; iii.a) SOCl2, DCE, rt, 1 h, b)AlCl3, ClCH2COCl, rt, 2 h, 1d 9%, 2d 71%; iv.a) NH2OH.HCl, CH3COONa.3H2O, H2O-MeOH-THF, 50°C, 2h, b) SOCl2, dioxane, 70°C, 6 h, 1e 40%, 2e 44%; v. DBU, water, THF, rt, 24 h, 1f 75%, 2f 80%

In the first step (Scheme 3), a propionic acid side chain was installed at the carbon position 3 of 1a using acrylic acid and acetic anhydride.18 Then the indole nitrogen of 1b, 2b was protected with a pivaloyl group. The next key step in the synthesis is a Friedel-Crafts acylation with intra-molecular cyclization. Teranishi and his coworkers19 had synthesized 2d (Uhle’s ketone) from acyl chloride derivative of 2c using AlCl3 and chloraacetyl chloride additive in 78% yield. The electron withdrawing ability of the pivaloyl amide helps in reducing nucleophilic activity of C2 and the tert-butyl group hinders C2 from electrophile attack which proved viable for indole-3-ylpropionic acids. With 6-fluoroindole-3-ylpropionic acid, Friedel-Crafts acylation of 1c gave the desired 1d in 9% yield which is quite low compared to that of 2d. Attempts were made to improve the cyclization yield of 1d (Table 1) but in most cases either the formation of side product 1j is noticed or starting materials were degraded. The exception was found in the entry 8 (40% yield, Supporting information, Scheme 3). We presumed that the formation of 1j is due to the nucleophilicity of the C2 position of the indole scaffold, here the effect is more pronounced due to the negative inductive effect of fluorine on the condensed benzo moiety. Changing the protecting group from pivaloyl to tosyl or bulky TBDPS did not improve the yield (Table 1, entries 3, 4). Neither using the milder Lewis acid boron trifluoride nor the super strong triflic acid (entries 5, 6) gave the desired product which limited our means for optimization so that we decided to live with 9% yield for 1d and proceed to make the final radioligand.

Entry

indole 1c

Conditions

t/h

Product / %a

1

R, R1 = H

i.SOCl2 ii.AlCl3

3

1j (70)

2

R= Piv R1=H

i.SOCl2 ii.AlCl3

3

1d (9), 1j (57)

3

R= Ts R1=H

i.SOCl2 ii.AlCl3

15

1j (24)

4

R=TBDPS R1=H

i.SOCl2 ii.AlCl3

5

-

5

R=Piv R1=H

Triflic acid 0-rt

10

-

6

R=-Piv R1=H

i.SOCl2 ii.BF3(OEt)2

16

1j (18)

7b

R=Ts R1=Br

i.SOCl2 ii.AlCl3

5

-

8b

R=Ts R1=Cl

i.SOCl2 ii.AlCl3

5

1r (40)

x Reactions were performed with Indole (0.3 mmol), SOCl2 (1.2 mmol), AlCl3 (0.6 to 1.2 mmol), rt, DCE (5 mL), n≥2, aisolated yield, TBDPS tert-butyl diphenyl silyl, Ts tosyl; bSupporting information

The next steps in the synthesis of 1 and 2 are bromination, Suzuki coupling and reductive amination (Scheme 4). The precursor for radiolabelling 1i was made from 1h via reductive amination of aldehyde to primary amine and labelled with radiomethylation reagent, [3H]methyl nosylate (Scheme 5).

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ACS Chemical Neuroscience Scheme 4: Final synthesis of 1 and 2

Reagent and conditions: i. Pyr.HBr3, DCM-THF, 0°C-rt, 2 h, 1g 69%, 2g 77%; ii. 4-formaylphenylboronic acid, Pd(PPh3)4, Na2CO3, dioxane, 90°C, 12 h, 1h 65%, 2h 70%; iii. a) 1M MeNH2 (MeOH), rt, 2 h, b) NaBH4, MeOH-THF, 0°C-rt, 1 66%, 2 71%

Catalytic hydrogenation (Raney Ni-H2, Pd/C-H2, Pd/Cammonium formate) of aldoxime derivative of 1h gave 1i in low yields probably due to the debenzylation side reaction. But using Zn dust and HCl, the aldoxime derivative of 1h gave 1i in very good yield. Scheme 5: Synthesis of precursor 1i and [3H]1

O

F

H N

O

O O S CT3 O

H N

i N H 1h

O

F

O

O2 N N H

NH 2

F

H N

N H

[ 3 H]1

T

NH T T

1i

Reagents, conditions; i. a) NH2OH.HCl, CH3COONa.3H2O, H2OMeOH, 50°C, 1 h, b) Zn, conc.HCl, EtOH, 0°C-rt, 3 h, 1i 76%

A series of small scale (3 µmol) experiments (Supporting information, Table 1) were performed to obtain the desired monomethylated 1 and to suppress the formation of di/tri methylated products under labeling conditions. The optimized conditions were used to prepare [3H]1. [3H]methylation of 1i was performed using [3H]methyl nosylate as methylatingagent. The specific activity of [3H]1 is 82.8 Ci/mmol with radiochemical purity 98.8% (Supporting information).

Autoradiography At this point, we developed autoradiography conditions and tested the PARP saturation by [3H]1 in two different types of rodent brains, brains from wild type and transgenic mice carrying the Arc-Swe double mutation were used.21,22 The brain sections (0.02 mm thick) were thaw mounted onto a microscopic slides and utilized for concentration dependent binding of [3H]1 at increasing concentration of 1; see the supporting information for experimental details. [3H]1 was found to bind reversibly to a single site and allowed for quantification of PARP in e.g. hippocampus and cerebellar cortex (Figure 1). Figure 1 illustrates the PARP binding profile of [3H]1 in absence (A, C) and presence (B, D, left) of 1. The highest binding densities of [3H]1 of all areas examined were found in the hippocampal dentate gyrus and cerebellar cortex regions in both the models (Figure 1 A,C). Areas such as cerebral cortex, and thalamus were found to bind negligible amounts at all radioligand concentrations proving low non-specific binding. The presence of PARP activity in hippocampal dentate gyrus has been demonstrated previously using PAR in situ (PARIS) or in situ end labeling techniques (ISEL).23 Northern

Figure 1 Autoradiography images from saturation binding with [3H]1 and competition with 1. (A) Wild type, [3H]1 total binding (1 nM, control) (B) Comparison of [3H]1 binding in presence (left), absence of 1µM of 1 (right) (C) Transgenic type, [3H]1 binding (1 nM, control) (D) Comparison of [3H]1 binding in presence (left), absence of 1 µM of 1 (right) DG Dentate Gyrus of hippocampus, CC Cerebellar cortex; n=3

blotting and in situ hybridization methods have also provided evidence on PARP mRNA expression in the dentate gyrus of the hippocampus.24 Using Western blot analysis, Joanna et al, reported PARP expression in hippocampus, cerebellum and cerebral cortex regions.25 As it can be seen in Figure 1, the addition of non-radioactive 1 (1 µM) saturated the [3H]1 specific and selective binding in those regions, which highlights the excellent non-specific binding of rucaparib. Concentration dependent binding of [3H]1 was measured and the dissociation constant (Kd) and Bmax were determined. The regional distribution of [3H]1 is in good agreement with PARP distribution in rodent brain.23-25,27-28 Non-linear regression analysis of the autoradiographic data (Table 2) indicated that the binding was to single class of binding sites in both key regions, the cerebellar cortex and the dentate gyrus, implicated in PARP-related brain damage in previous studies as explained above. Specific binding of [3H]1 was reproducibly saturable and nonspecific binding increased with the concentrations of [3H]1 under the assay conditions used. The Hill slopes of data derived from Prism program were 0.75±0.1 suggesting that the ligand binds to one site with no major cooperativity.26 When the binding of [3H]1 was examined between the two different models under study, the transgenic models has shown relatively lower PARP densities in the two regions. We presumed this reflects higher relative vulnerability of the trans-



genic animals to develop neurodegenerative phenotypes. Or make them vulnerable to other insults to cell homeostasis caused by the mutations. The PARP up-regulation also depends on the brain pathophysiology.27 Evidently, alterations in PARP activity were indicated in human postmortem sections of Alzheimer’s brains.9,10

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Conflicts of interest None to be declared.

Notes There is no competing financial interest

REFERENCES Table 2 Saturation isotherm data Type Wild Tg

Region

Bmax (pmol/mg)

Kd (nM)

Cerebellar cortex

8.1±0.3

1.11±0.07

Dentate gyrus

7.2±0.5

1.06±0.16

Cerebellar cortex

7.4±0.4

1.15±0.12

Dentate gyrus

6.1±0.3

0.99±0.09

CONCLUSION So far our understanding of the role of PARP in brain was generated from histochemical studies on PARP activation or RNA-expression in rodent brains.23-25,27-28 The results described here with [3H]1 allow for direct assessment of PARPprotein binding by quantitative autoradiography to measure [3H]1 binding to PARP protein throughout the brain. The autoradiography provides quantitative measure of protein density, which adds a new dimension to PARP related research. As a proof-of-principle we chose to measure PARP saturation binding in brain regions associated with functional PARP-1 in wildtype and transgenic mice. The current observations and the previous, related evidences may suggest PARP association with neuronal damage,28,29 particularly in the hippocampal dentate gyrus. Dentate gyrus along with Olfactory bulb and cerebellum are known to be the regions for neurogenesis in adult brains.30-32 Proper pharmacological investigations of functional PARP protein in brain may provide not only a way to the neuroprotection but also a comprehensive understanding to the relation between DNA damage/repair and neurogenesis.

ASSOCIATED CONTENT Supporting information Experimental procedures and analytical data and supplemental graphs. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Author contributions S.R.A: Chemistry, autoradiography, data evaluation, manuscript writing, supporting information compilation. P.J.R: Study design, data evaluation, final manuscript compilation, funding

Funds and acknowledgements This study was funded by the Faculty of Mathematics and Natural sciences, University of Oslo (PJR). Kjemisk institute, UiO is thanked for the PhD fellowship (SRA). Corresponding author Patrick J. Riss Tel: +47 22857673. E-mail: [email protected]

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Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis

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