TDP-43 binding compounds and TDP-43 positron emission tomography imaging ligands

Abstract

The present invention relates to novel, selective compounds with affinity to TDP-43, and to novel, selective radiolabelled TDP-43 ligands which are useful for imaging TDP-43 aggregates, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging TDP-43 aggregates in a tissue or a subject, in vitro or in vivo, and to precursors of said compounds.

Description

TDP-43 BINDING COMPOUNDS AND TDP-43 POSITRON EMISSION TOMOGRAPHY IMAGING LIGANDSFIELD OF THE INVENTION

[0001] The present invention relates to novel, selective compounds with affinity to TDP-43, and to novel, selective radiolabelled TDP-43 ligands which are useful for imaging TDP-43 aggregates, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging TDP-43 aggregates in a tissue or a subject, in vitro or in vivo, and to precursors of said compounds.BACKGROUND OF THE INVENTION

[0002] TAR (transactive response) DNA-binding protein 43 kDa (TDP-43), encoded by the TARDBP gene, is a 43kDa nuclear protein that belongs to the heterogeneous nuclear ribonucleoproteins (hnRNPs) family that binds RNA (Krecic A, Swanson M. hnRNP complexes: composition, structure, and function. CurrOpinCellBiol.1999;11 (3).

[0003] Under pathological conditions, cleavage, hyperphosphorylation, ubiquitination and cleavage into C-terminal fragments (CTF) of TDP-43 can occur leading to cytoplasmic accumulation and aggregation in the cytoplasm. Pathological TDP-43 is found in a range of neurological diseases even if the underlying causes of the diseases are not known.

[0004] Positron Emission Tomography (PET) is a non-invasive imaging technique used to identify a wide array of diseases and is ideally suited for assessing neurological disorders. This technique offers the highest spatial and temporal resolution of all nuclear imaging techniques and has the added advantage that it can allow for true quantification of tracer concentrations in tissues.

[0005] Despite TDP-43 pathological prevalence in a range number of neurodegenerative diseases, no adequate positron emission tomography radiotracers with high selectivity are available for imaging of TDP-43 aggregates. Consequently, there is a need for PET tracers that bind with high affinity and selectivity (over other pathological neurodegenerative aggregates, such as beta amyloid, PHF-tau, alpha-synuclein) to TDP-43 aggregates which may be used as a diagnostic tool for early disease detection

[0006] The present invention provides 4-substituted 2-aminoquinazoline compounds with binding affinity to TDP-43 aggregates. In addition, the present invention provides novelradiolabelled compounds that are useful as PET tracers for imaging TDP-43 aggregates, which exhibit a good balance of properties, including, but not limited to, high affinity and selectivity towards TDP-43 aggregates, and synthetic accessibility. Some quinazoline containing compounds have been disclosed in the art, associated with kinase inhibition activity, and the field of oncology treatment. Compounds of the present invention have not been identified to exhibit such activity at 1 pM in a 374 kinase panel.SUMMARY OF THE INVENTION

[0007] It is therefore an object of the present invention to provide novel compounds with binding affinity to TDP-43, in particular novel radiolabelled compounds useful as TDP-43 radiotracers. Therefore, in one aspect, the present invention relates to a compound havingor a stereoisomeric form thereof, whereinR1is [19F] or [18F];R2is selected from the group consisting of (a), (b), (c), (d) and (e)whereinX represents CR2aR2bor NR2c; wherein m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, CF3, CH2CHF2, CH2CF3, Si(CH3)3, or N(CH3)2;R2crepresents CH2Si(CCR2aR2btogether formZ represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; orSiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

[0008] In particular, the present invention relates to a compound of Formula (I’)or a stereoisomeric form thereof, whereinR1is [18F];R2is selected from the group consisting of (a), (b), (c), (d) and (e)whereinX represents CR2aR2bor NR2c; wherein m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, CF3, CH2CHF2,Z represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; orSiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the invention relates to precursor compounds for the synthesis of the compounds of Formula (I) or (I’), as previously defined. Thus, the present invention also relates to a compound of Formula (P-l)

[0010] wherein LG is a suitable leaving group, and R2and R3are each as defined in Formula (I) or (I’), as described herein.

[0011] In (P-l), suitable leaving groups (LG) include Cl, and Br.

[0012] The invention also relates to a pharmaceutical composition comprising a compound of Formula (I) or (I’), in particular a compound of Formula (I’), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. In particular, said pharmaceutical composition is a diagnostic pharmaceutical composition. Said pharmaceutical composition is in particular, a sterile solution. Thus, illustrative of the invention is a sterile solution comprising a compound of Formula (I), in particular a compound of Formula (I’), as described herein.

[0013] The invention further relates to the use of a compound of Formula (I), in particular a compound of Formula (I’), as an imaging agent. Another aspect of the invention is the use of acompound of Formula (I), in particular a compound of Formula (I’), as described herein, for, or a method of, imaging a tissue or a subject, in vitro or in vivo.

[0014] In particular, the invention relates to a compound of Formula (I), in particular a compound of Formula (I’), for use in binding and imaging TDP-43 aggregates in a subject, and in particular the brain of a subject.

[0015] The invention also relates to a method for imaging a tissue or a subject, comprising contacting with or providing or administering a detectable amount of a labelled compound of Formula (I), in particular a labelled compound of Formula (I’), to a tissue, or a subject, and detecting the compound of Formula (I), in particular the compound of Formula (I’).

[0016] Further exemplifying the invention is a method of imaging a tissue, or a subject, comprising contacting with or providing to a tissue, or a subject, a compound of Formula (I), in particular a compound of Formula (I’), as described herein, and imaging the tissue, or subject with a positron-emission tomography imaging system. Further exemplifying the invention is a method of gathering data for the diagnosis of a TDP-43 related disorder, or a method of monitoring of the progression of a TDP-43 related disorder, or a method of monitoring treatment response of a TDP-43 related disorder, wherein the method comprises one or more of the following steps: (i) contacting with or providing or administering a detectable amount of a labelled compound of Formula (I), in particular a labelled compound of Formula (I’), as described herein to a tissue, or a subject, (ii) allowing the labelled compound of Formula (I), in particular the compound of Formula (I’), as described herein, to bind to any TDP-43 aggregates;(iii) detecting the labelled compound of Formula (I), in particular the compound of Formula (I’);(iv) correlating the presence or absence of labelled compound of Formula (I), in particular the compound of Formula (I’), as defined herein, with the presence or absence of TDP-43 aggregates in the tissue or subject.

[0017] Additionally, the invention refers to a process for the preparation of a compound ofor a pharmaceutically acceptable salt thereof as described herein, comprising the step of reacting a compound of Formula (P-l) with a source of [18F]fluoridewherein LG is a suitable leaving group, and R2and R3are as defined in Formula (I’) as described herein; under suitable reaction conditions.BRIEF DESCRIPTION OF THE FIGURES

[0018] Figure 1A shows human brain evaluation by Western blotting: pathological p-TDP-43 is present in cell cytosol and increased in patients with neurodegenerative disorder diagnosis, using Proteintech #22309-1-AP (antibody recognizing p-TDP43). In Figure 1 , RIPA means all cell fractions, CP means cytosol, CHB means chromatin, CellM means cell membrane, NEB means nuclear. Figure 1 B shows a summary of aggregate proteins on human brains from neurological disease patients (ND) and healthy controls (HC).

[0019] Figure 2A / B shows in vitro autoradiography (ARG) competition assays on human brain sections presenting TDP-43 pathology with self-blocking. Figure 2A: compound [18F]-1 ; Figure 2B: compound [18F]-3.

[0020] Figure 3 shows In vitro ARG of compound [18F]-1 (Figures 3A and 3B) on human brain sections with different neurological diseases (NC = normal control). In each of Figures 3A and 3B, top tables show the aggregated proteins (PHF-tau, A|3, aSyn, and phospho TDP-43) deposits in each brain detected by IHC, and bottom images show ARG data with / without selfblocking on adjacent sections. Figure 3A: blocking effects were found on all brain sections, lowest blocking effect was observed on normal brain section (30%) while 60-85% of selfblocking was observed on disease brain sections; the highest blocking effect was found on brain 15 sections (in which only TDP-43 aggregates were observed to be present).

[0021] Figure 4 shows In vitro ARG of compound [18F]-3 on human brain sections with different neurological diseases (NC = normal control). Top table shows the aggregated proteins (PHF-tau, Ap, aSyn, and phospho TDP-43) deposits in each brain detected by IHC. The bottom images show ARG data with / without self-blocking on adjacent sections. Blocking effects were found on all sections, lowest blocking effect was observed on normal brain section.

[0022] Figure 5 shows IC5o measurement of compound 1 by in vitro autoradiography (ARG) on frontal cortex section from brain samples presenting TDP-43 pathology. The result shows that compound 1 has a potency of 10 nM, which is similar to Kd(7.9 nM) measured by SPR assay.

[0023] Figure 6 shows Standardized Uptake Value (SUV) (Figure 6A) and ratio (SUVR) (Figure 6B) results from PET images of [18F]-1 in different regions of the brain and in total brain (Figure 6C) in normal Sprague Dawley rats.

[0024] Figures 7 and 8 show compound [18F]-1 results from PET imaging in human pTDP-43 expressing AAV-hSYN1-hTDP-43 (A315T / G348C) mouse model (model; C57BL6 mice injected with AAV9-hSYN1-(A315T / G348C) or AAV9-hSYN1-null (Dose: 3.4 x 1018GC / ml) in left frontal cortex (4 weeks post injection). Figure 7A: PET / CT and pTDP-43 IHC; Figure 7B: Time Activity Curve; Figure 8A: SUV Cortex Left Side TDP43 vs Null; Cortex Left vs Right in AAV-TDP43;Cortex Left vs Right in AAV-Null; Figure 8B: SUV Cerebellum Left Side TDP43 vs Right in AAV- Null; Cerebellum %SUVR Left TDP43 vs Right AAV-Null.

[0025] Figure 9A-B shows results from a PET imaging study with compound [18F]-1 in nonhuman primates (NHP). Compound [18F]-1 readily entered NHP brain and demonstrated a heterogeneous uptake. Peak standardized uptake value (SUV) up to ~2.5 g / mL at ~9 min (~3.1 % ID), followed by a moderate washout (whole-brain %ID at 60 min and 240 min was 2.0% and 0.7%, respectively. Tracer metabolized with ~20% and ~15% parent remaining at 30 min, and 180 min p.i., respectively. Plasma free fraction was not measured. [18F]-1 showed low nonspecific binding.

[0026] Figure 10 shows in vivo metabolism of compound [18F]-1 in rat: (A) standard, (B) Plasma, (C) Brain; no metabolites in rat brain (30 min post-injection were identified), and good stability was observed at 30 min (73% of parent peak remaining). In vitro, compound [18F]-1 was additionally found to have higher metabolic stability in human hepatocytes relative to rat and cynomolgus monkey.

[0027] In the figures, aggregation in the brain ID numbers is represented ++++, +++, ++, + for presence of aggregation, and - for absence of aggregation.DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention provides novel compounds with binding affinity to TDP-43, in particular novel radiolabelled compounds useful as TDP-43 radiotracers having Formula (I)or a stereoisomeric form thereof, whereinR1is [19F] or [18F];R2is selected from the group consisting of (a), (b), (c), (d) and (e)whereinX represents CR2aR2bor NR2c; wherein m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, CF3, CH2CHF2,Z represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; orSiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

[0029] In a particular embodiment, the invention relates to compounds of Formula (I)or a stereoisomeric form thereof, wherein R1is [19F] or [18F];R2is selected from the group consisting of (a), (b) and (c)whereinX represents CR2aR2bor NR2c; m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, Si(CH3)3, or N(CH3)2;R2crepresents CH2Si(CR2aR2btogether formZ represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; orSiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

[0030] In a particular embodiment, the invention relates to compounds of Formula (I’)or a stereoisomeric form thereof, wherein R1is [18F];R2is selected from the group consisting of (a), (b) and (c)(a) (b) (c) whereinX represents CR2aR2bor NR2c; m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, Si(CH3)3, or N(CH3)2;R2crepresents CH2Si(CR2aR2btogether formZ represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; orSiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

[0031] In a further embodiment, the compound of Formula (I) is in particular a compound of Formula (l-a), (l-b) or (l-c)or a stereoisomeric form thereof, whereinR1is [19F] or [18F];X represents CR2aR2bor NR2c; wherein m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, Si(CH3)3, or N(CH3)2;R2crepresents CH2Si(CR2aR2btogether formZ represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; orSiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

[0032] In a further embodiment, the invention relates to a compound of Formula (l’-a), (l’-b) or (I’-c)or a stereoisomeric form thereof, whereinR1is [18F];X represents CR2aR2bor NR2c; wherein m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, Si(CH3)3, or N(CH3)2;R2crepresents CH2Si(CR2aR2btogether formZ represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; orSiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

[0033] The compound of Formula (P-l) is, in particular, a compound of Formula (P-la), (P-lb), or (P-lc)wherein X, Z, m, n, p, q, R3, and LG are as described herein.

[0034] Particular intermediates or precursors of compound of Formula (I’) are, for example:wherein LG is Cl or Br.

[0035] In a particular embodiment, the invention relates to a process of preparing the compound of Formula (P-la’)comprising the step of reacting 2-chloro-4-(3-ethyl-1-azetidinyl)quinazoline with either 6-chloro- 3-pyridinemethanamine or 6-bromo-3-pyridinemethanamine, under suitable reaction conditions.

[0036] Suitable reaction conditions include for example, heating at an appropriate temperature, in a protic solvent, for example an alcohol, in particular ethanol.

[0037] In a particular embodiment, the invention relates to a process of preparing compoundcomprising the step of reacting 2-chloro-4-(4,4-dimethyl-1 ,4-azasilinan-1-yl)quinazoline with either 6-chloro-3-pyridinemethanamine or 6-bromo-3-pyridinemethanamine, under suitable reaction conditions.

[0038] Suitable reaction conditions include for example, heating in a protic solvent, for example an alcohol, in particular ethanol.

[0039] In a particular embodiment, the invention relates to the compound 2-chloro-4-(4,4- dimethyl-1 ,4-azasilinan-1 -yl)quinazoline:

[0040] In another embodiment, the invention relates to a process or method of preparingcomprising the step of reacting the compound (P-la’) with a source of [18F]fluoridewherein LG is a leaving group selected from Cl and Br, in particular Cl; under suitable reaction conditions.

[0041] In another embodiment, the invention relates to a process or method of preparing compound ([18F]-3)comprising the step of reacting the compound (P-l b’) with a source of [18F]fluoridewherein LG is a leaving group selected from Cl and Br, in particular Br; under suitable reaction conditions.

[0042] In a particular embodiment, the compound (P-lb’) according to the invention is the

[0043] Suitable reaction conditions in the above embodiments comprise, for example, reacting the compound of Formula (P-la’) or (P-lb’) with the indicated reagent, in the presence of a source of [18F]F, for example 4,7,13,16,21 ,24-hexaoxa-1 ,10-diazabicyclo[8.8.8]hexacosane potassium fluoride-[18F] (1 :1) (also referred to as [18F]KF.K222, or Kryptofix® 222). This reagent can be activated, using Kryptofix 2.2.2-[18F]fluoride-potassium carbonate, whereby potassium carbonate is used as the base and Kryptofix® 222 is used as the phase transfer agent. Suitable reaction conditions further include, those appropriate for nucleophilic substitution known in the art, for example, using DMSO or DMF as solvent, in particular DMSO, under conventionalheating or microwave irradiation (e.g. 50 W), for example at about 90-160 °C, or at about 120- 160 °C, in particular at about 160 °C, for a sufficient period of time to enable the reaction to proceed to completion, for example 10 min, for example, with the reaction being performed under microwave irradiation.

[0044] As already mentioned, the compound of Formula (I), in particular the compound of Formula (I’), and compositions comprising the compound of Formula (I), in particular the compound of Formula (I’), can be used for imaging a tissue, or a subject, in vitro or in vivo. In particular, the invention relates to a method of imaging or quantifying TDP-43 aggregates in a tissue, or a subject in vitro or in vivo.

[0045] In particular, the method of imaging TDP-43 aggregates comprises providing a subject, in particular a patient, with a detectable quantity of a compound of Formula (I), in particular a compound of Formula (I’).

[0046] Further, the invention relates to a method of imaging TDP-43 aggregate deposits comprising the steps of providing a subject with a detectable quantity of a compound of Formula (I), in particular a compound of Formula (I’), allowing sufficient time for the compound of Formula (I), in particular the compound of Formula (I’), to be associated with TDP-43 aggregate deposits, and detecting the compound associated with TDP-43 aggregate deposits. The result may be useful as a diagnostic tool for early disease detection in the subject.

[0047] When the method is performed in vivo, the compound of Formula (I), in particular the compound of Formula (I’), can be administered intravenously, for example, by injection with a syringe or by means of a peripheral intravenous line, such as a short catheter. The compound of Formula (I), in particular the compound of Formula (I’), or a sterile solution comprising a compound of Formula (I), in particular a compound of Formula (I’), may in particular be administered by intravenous administration in the arm, into any identifiable vein, in particular in the back of the hand, or in the median cubital vein at the elbow.

[0048] Thus, in a particular embodiment, the invention relates to a method of imaging a subject, comprising the intravenous administration of a compound of Formula (I), in particular a compound of Formula (I’), as defined herein, or a composition, in particular, a sterile formulation, comprising a compound of Formula (I), in particular a compound of Formula (I’), to the subject, and imaging the subject with a positron emission tomography imaging system.

[0049] Furthermore, the invention relates to a method of using a radiolabelled compound of Formula (I), in particular of Formula (I’) as described herein, comprising introducing into a subject a detectable quantity of the radiolabelled compound, allowing sufficient time for the radiolabelled compound to bind to the TDP-43 aggregates and then detecting the radiolabelled compound in the brain of the subject.

[0050] In a further embodiment, the invention relates to a method of quantifying TDP-43 aggregation deposits in a subject, comprising the intravenous administration of a compound ofFormula (I), in particular a compound of Formula (I’), or a composition comprising a compound of Formula (I), in particular a compound of Formula (I’), to the subject, and imaging with a positron-emission tomography imaging system.

[0051] The compound is provided to a subject in a detectable quantity and after sufficient time has passed for the compound to become associated with the TDP-43 aggregation deposits, the labelled compound is detected noninvasively.DEFINITIONS

[0052] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0053] The term “Ci.4alkyl” shall denote a straight or branched saturated alkyl group having 1 , 2, 3 or 4 carbon atoms, respectively e.g. methyl, ethyl, 1 -propyl, 2-propyl, butyl and the like.

[0054] The symbol” represents a chemical bond with point of attachment.

[0055] Addition salts of the compounds according to the invention also intended to be encompassed within the scope of this invention.

[0056] Acceptable salts of the compounds of the invention are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention. The pharmaceutically acceptable salts are defined to comprise the therapeutically active non-toxic acid addition salt forms that the compounds according to the invention are able to form. Said salts can be obtained by treating the base form of the compounds according to the invention with appropriate acids, for example, inorganic acids, for example hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid; organic acids, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

[0057] Conversely, said salt forms can be converted into the free base form by treatment with an appropriate base.

[0058] In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

[0059] The term "subject" as used herein, refers to a human, who is or has been the object of treatment, observation or experiment. Unless otherwise stated, “subject” includes non- symptomatic humans, presymptomatic humans and human patients.

[0060] In a further embodiment, the invention relates to a compound of Formula (I) as defined herein, wherein R1is [19F], or simply referred to as F, and the rest of variables are as described herein.

[0061] In a further particular embodiment, the compound of Formula (I) is any one of the following compounds:or a pharmaceutically acceptable salt or a solvate thereof.PREPARATION

[0062] The compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person. In particular, the compounds can be prepared according to the following synthesis methods.RADIOSYNTHESIS( - )

[0063] Compounds of Formula (I) as disclosed herein can be prepared by a reaction of a compound of Formula (P-I) as disclosed herein, under suitable reaction conditions such as nucleophilic substitution conditions. Such reaction conditions include, for example, reacting the compound of Formula (P-I) with a source of [18F]F, for example 4,7,13,16,21 ,24-hexaoxa-1 ,10- diazabicyclo[8.8.8]hexacosane potassium fluoride-[18F] (1 :1) (also referred to as [18F]KF.K222, or Kryptofix® 222). This reagent can be activated, using Kryptofix 2.2.2-[78F]fluoride-potassium carbonate, whereby potassium carbonate is used as the base and Kryptofix® 222 is used as the phase transfer agent. Suitable further reaction conditions include, for example, dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) as solvent, in particular DMSO, under conventional heating or microwave irradiation (e.g. 50 W), for example at about 90-160 °C, or at about 120-160 °C, in particular at about 160 °C, for a sufficient period of time to enable the reaction to proceed to completion, for example 10 min, for example, with the reaction being performed under microwave irradiation.SYNTHESIS OF INTERMEDIATE COMPOUNDSPROCEDURE 1

[0064] Intermediate 1 : 2-Chloro-4-(3-ethylazetidin-1-yl)quinazoline (1-1)A solution of N,N-diisopropylethyl amine (DIPEA) (3.588 ml_, 20.599 mmol) in acetonitrile (20 mL) was added dropwise over the course of 5 min to a round-bottomed flask containing a white suspension, consisting of 2,4-dichloroquinazoline (0.410 g, 2.060 mmol) and 3-ethylazetidine trifluoroacetate (0.451 g, 2.266 mmol) in acetonitrile (20 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 hr. The mixture was then diluted with ethylacetate and washed with water, the organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuo to give intermediate 1-1 (0.424 g, 79%) as a beige solid that wasused in the next step without further purification. Mass spectrum (electrospray ionization (ESI), m / z): Calcd. For CI3HI4CIN3, 247.1 , found [M+H]+, 248.21H NMR (300 MHz, DMSO-d6) d 7.98 (d, J = 8.3 Hz, 1 H), 7.78 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.64- 7.59 (m, 1 H), 7.47 (ddd, J = 8.3, 7.0, 1 .2 Hz, 1 H), 5.07 - 3.68 (m, 4H), 2.80 - 2.63 (m, 1 H), 1 .67 (p, J = 7.3 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H).

[0065] Following a procedure analogous to that described for 1-1 , the following compounds were alsoPROCEDURE 2:

[0066] Intermediate 1-15: N-((6-Chloropyridin-3-yl)methyl)-4-(3-ethylazetidin-1-yl)quinazolin-2- amine(6-Chloropyridin-3-yl)methanamine (0.645 g, 4.521 mmol) was added to a 20 mL microwave vial containing a white suspension, consisting of 1-1 (0.280 g, 1.130 mmol) and isopropylalcohol (15ml_), then sealed and stirred at 150 °C for 1 h under microwave irradiation. The orange reaction mixture was diluted with ethylacetate (75 mL) and washed with water (50 ml_), the organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuo to give an orange solid. The solid was then subjected to silica gel chromatography (25 g, silica irregular 40-60 pm, gradient 0-10% MeOH / dichloromethane(DCM)) to give 1-15 (0.286 g, 71 %) as a white solid. Calcd. For C19H20CIN5, 353.1407, found [M+H]+, 354.1262.1H NMR (400 MHz, DMSO-d6) 8.40 (d, 1 H, J=2.2 Hz), 7.82 (dd, 1 H, J=2.4, 8.2 Hz), 7.72 (d, 1 H, J=8.3 Hz), 7.49 (t, 1 H, J=7.2 Hz), 7.44 (d, 1 H, J=8.2 Hz), 7.26 (br d, 2H, J=8.1 Hz), 7.02 (t, 1 H, J=7.6 Hz), 4.49 (br d, 4H, J=6.2 Hz), 4.01 (br s, 2H), 2.5-2.7 (m, 1 H), 1.64 (quin, 2H, J=7.4 Hz), 0.89 (t, 3H, J=7.3 Hz)PROCEDURE 3:

[0067] Intermediate P-lb’: N-((6-Bromopyridin-3-yl)methyl)-4-(4,4-dimethyl-1 ,4-azasilinan-1- yl)quinazolin-2-amine (P-lb’)(6-Bromopyridin-3-yl)methanamine (385 mg, 2.06 mmol) was added to a 20 mL microwave vial containing a colorless suspension, consisting of I-3 (300 mg, 1.03 mmol) and isopropylalcohol (8.3 mL), then sealed and stirred at 150 °C for 1 h under microwave irradiation to give a yellow solution. The yellow solution was concentrated to dryness in vacuo to give pale yellow solid, which was subjected to flash column chromatography (12 g, irregular 40-60 urn; 0-30 % DCM- MeOH(9:1) / DCM) to afford P-lb’ (146 mg, yield: 31 %) as a white solid. Calcd. For C2oH24BrN5Si, 441.098, found [M+H]+, 442.1001H NMR (400 MHz, DMSO-d6) d ppm 12.76 (s, 1 H), 8.41 (d, J = 2.3 Hz, 1 H), 7.95 (s, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 2H), 7.62 (d, J = 8.2 Hz, 1 H), 7.52 (d, J = 7.7 Hz, 1 H), 7.34 (s, 1 H), 4.62 (d, J = 5.8 Hz, 2H), 4.14 - 4.00 (m, 4H), 0.99 - 0.91 (m, 4H), 0.14 (s, 6H).PROCEDURE 4:

[0068] Intermediate 1-16: 2-(1-(2-((Pyridin-3-ylmethyl)amino)quinazolin-4-yl)piperidin-4-yl)ethan-1-OlA solution of 2,4-dichloroquinazoline (500 mg, 2.51 mmol) in 25 mL of acetonitrile (MeCN) was added to 4-piperidineethanol (508 mg, 3.93 mmol). After the reaction mixture was stirred at room temperature for 2 h, the solvent was removed under vacuum. CombiFlash (SiO2, 12g, DCM:EtOAc 0 to 50% over 12 min) afforded 2-(1-(2-chloroquinazolin-4-yl)piperidin-4-yl)ethan-1- ol with the yield of 83.8%. 2-(1-(2-Chloroquinazolin-4-yl)piperidin-4-yl)ethan-1-ol (100 mg, 0.34 mmol) and pyridine-3-ylmethanamine (108.1 mg, 0.51 mmol) was added to microwave vial in 2.6 ml of ethanol. The reaction mixture was sealed and heated to 150 °C for 20 min before cooling down to room temperature. CombiFlash (SiO2x 4 g, DCM:MeOH, 0 to 20% over 12 min) afforded 1-16 with the yield of 80.0%.PROCEDURE 5:

[0069] Intermediate 1-17: 2-(1-(2-((Pyridin-3-lmethyl)amino)quinazolin-4-yl)piperidin-4-yl)ethyl 4- methylbenzenesulfonateA solution of 1-16 (58 mg, 0.16 mmol) in 0.58 ml dichloromethane (DCM) at 0 °C was treated with triethylamine (66.5 pL, 0.48 mmol) and tosylate chloride (TsCI, 60.8 mg, 0.32 mmol). The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixturewas purified by CombiFlash 2 x 4g SiO2(DCM:MeOH) 0 to 20% over 8 min. 1-17 (82.6 mg, 0.13 mmol) was obtained in the yield of 80.3%.PROCEDURE 6:

[0070] Intermediate 1-18: 4-(4-(2-Bromoethyl)piperidin-1-yl)-N-(pyridine-3-ylmethyl)quinazolin-2- amineTo a solution of 1-16 (70 mg, 0.19 mmol) in carbon tetrabromide (191.6 mg, 0.58 mmol) and dichloromethane (DCM, 3.5 ml) was added triphenylphosphine (TPP, 111.1 mg, 0.42 mmol).The mixture was slightly stirred for 1 hour. Then the reaction solvent was evaporated.CombiFlash (12g SiO2, DCM:MeOH 0-20% over 8 min) afforded 1-18 (82.1 mg, 97.4%).PREPARATION OF FINAL COMPOUNDSPROCEDURE 7:

[0071] Example 1 : 4-(3-Ethylazetidin-1-yl)-N-((6-fluoropyridin-3-yl)methyl)quinazolin-2-amine (1)(6-Fluoropyridin-3-yl)methanamine (0.285 g, 2.261 mmol) was added to a 20 mL microwave vial containing a white suspension, consisting of 1-1 (0.140 g, 0.565 mmol) and isopropylalcohol (7 mL), then sealed and stirred at 150 °C for 1 h under microwave irradiation. The orange reaction mixture was diluted with ethylacetate (30 mL) and washed with water (30 mL), the organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuo to give an orange solid. The solid was then subjected to silica gel chromatography (12 g, silica irregular 40-60 pm, gradient 0-10% MeOH / DCM) to give 1 (0.087 g, 45 %) as a beige solid. Calcd. For C19H20FN5, 337.1703, found [M+H]+, 338.1562.1H NMR (400 MHz, DMSO-d6) d ppm 0.88 (t, J=7.30 Hz, 3 H) 1.63 (quin, J=7.41 Hz, 2 H) 2.60 - 2.69 (m, 1 H) 4.01 (br s, 2 H) 4.49 (br d, J=6.20 Hz, 4 H) 6.98 - 7.03 (m, 1 H) 7.10 (dd, J=8.44, 2.72 Hz, 1 H) 7.16 - 7.23 (m, 1 H) 7.26 (br d, J=8.30 Hz, 1 H) 7.44 - 7.52 (m, 1 H) 7.71 (d, J=8.11 Hz, 1 H) 7.95 (td, J=8.30, 2.48 Hz, 1 H) 8.21 (s, 1 H)

[0072] Following a procedure analogous to that described for 1 , the following compounds were also synthesized.PROCEDURE 8:

[0073] Example 15: 4-(3-Ethylazetidin-1-yl)-6-fluoro-N-((6-fluoropyridin-3-yl)methyl)quinazolin- 2-amine (15)A solution of 3-ethylazetidine trifluoroacetic acid [1909337-74-1] (42 mg, 0.21 mmol) in DMSO (1 mL) followed by DIPEA [7087-68-5] (251 .52 pL, 0.74 g / mL, 1 .44 mmol) was added to 2,4-dichloro- 6-fluoroquinazoline (44.47 mg, 0.21 mmol) in a sealed vial under N2. The mixture was stirred at rt for 2h. Then a solution of (6-fluoropyridin-3-yl)methanamine [205744-17-8] (65 mg, 0.52 mmol) in DMSO (0.5 mL) was added. Then the mixture was stirred at 150°C for 90 min. The solution was purified by reverse phase high performance liquid chromatography (RP HPLC) (Conditions: Stationary phase: Sunfire™ Prep C18 30 x 100 mm 5 pm. Mobile phase: 0.1% HCO2H solution in H2O and CH3CN) to yield 15 (37.8 mg, yield 49%). Calcd. For Ci9Hi9F2N5, 355.16, found [M+H]+, 356.3.1H NMR (400 MHz, DMSO-d6) d ppm 8.19 - 8.25 (m, 1 H) 7.92 - 8.02 (m, 1 H) 7.44 - 7.65 (m, 2 H) 7.35 - 7.44 (m, 1 H) 7.06 - 7.19 (m, 1 H) 4.37 - 4.75 (m, 4 H) 3.92 - 4.23 (m, 2 H) 2.62 - 2.71 (m, 1 H) 1 .57 - 1 .71 (m, 2 H) 0.86 - 0.94 (m, 3 H).

[0074] Following a procedure analogous to that described for 15, the following compounds wereRADIOSYNTHESIS OF COMPOUND [18F]-(1)

[0075] Synthesis of [18F]-1 was carried out using a Synthra RNP|USresearch automated synthesizer.

[18] Fluoride was trapped in a vial on quaternary methylammonium (QMA) anion exchange cartridge. A solution of K2CO3an Kryptofix® 222 K222 (3 mg / 15 mg in 900 pL CH3CN and 100 pL water) was used to elute the

[18] Fluoride into the reactor 1 of the Synthra RNP|USResearch module. The solution was evaporated by heating at 80 °C for 5 min under vacuum and a stream of nitrogen. Acetonitrile (1 mL) was added to reactor 1 and evaporation was continued at 100 °C for 5 min under vacuum and nitrogen flow. Final evaporation was carried out at 110 °C for 3 min under vacuum. The reactor was cooled to 50 °C. A solution of precursor (N-((6-chloropyridin-3-yl)methyl)-4-(3-ethylazetidin-1-yl)quinazolin-2-amine (1-15), 2.9- 4.2 mg) in anhydrous DMSO (0.75 mL) was added to the reactor 1 and the mixture was heated at 180 °C for 10 min. The reactor was cooled to 50 °C, diluted with 25% CH3CN in water (3.5 mL) and the contents were transferred via syringe pump onto the HPLC injector loop for purification.

[0076] Purification was performed with the HPLC conditions listed below. The fractions containing [18F]-(1) were collected in the HPLC collection flask which contained 35 mL of HPLC grade water to dilute the product. The diluted product mixture was passed through a C18 Sep- Pak light cartridge and eluted with 0.5 mL of EtOH followed by 4.5 of saline into a mixing flask which was then transferred to the product vial.

[0077] The analytical method to determine radiochemical purity, specific activity and radiochemical impurities was performed using by comparison to cold reference standard using a co-injection method. The radiochemical identity was defined by relative retention time (RRT) to the cold reference standard between 0.9 and 1.1.

[0078] HPLC conditionsPreparatory HPLCAnalytical HPLC

[0079] The entire process was completed in approximately 1-1 .5 h including quality control. The radiochemical yield was 18-36%, in particular 27.7±6.5% (n=8) (decay corrected to end-of- synthesis (EOS)) with the radiochemical purity of >96%, in particular >95% (n=8) and the specific activity was > 1000 Ci / mmol, in particular 1415±384 mCi / pmol (n=8).RADIOSYNTHESIS OF COMPOUND [18F]-3

[0080] Radiosynthesis of [18F]-3 was performed in an analogous manner to that described for [18F]-1 above, starting from P-lb’, in a single step in moderate yield (>7.6%), high radiochemical purity (>95%), and good specific activity (1201 ± 878.3 mCi / mmol). [18F]-3 exhibited excellent in vitro radiochemical stability and the radiochemical purity was measured to be >95% at 4 hours after EOS.

[0081] LIQUID CHROMATOGRAPHY MASS SPECTROMETRY (LCMS)DAD = diode array detection, MeCN = acetonitrile, MSD = mass selective detector, TFA =

[0082] Table 1 . ANALYTICAL DATA. LCMS: [M+H]+means the protonated mass of the free base of the compound, Rtmeans retention time (in min), method refers to the method used for LCMS.For someIN VITRO AUTORADIOGRAPHY (ARG)

[0083] Specific binding of [18F]-1 was evaluated using in vitro autoradiography (ARG) on human brain sections including different pathologies and normal control.

[0084] To conform the specific binding of tracer, in vitro autoradiography was performed on sections of human brain with different diseases. Each air-dried frozen section was incubated with 200 pCi / mL of [18F]-labelled tracer in incubation buffer (5%DMSO and 5%EtOH in 1xphosphate buffer saline (PBS)) at room temperature for 60 minutes and then washed for 2 minutes in PBS, for 1 minutes in 30% ethanol / PBS, for 1 minute in 50% ethanol / PBS, and for 2 minutes in PBS to remove unbound tracer. After drying, the labelled section was exposed to a phosphor screen (GE, US) in a cassette in dark overnight. Autoradiographic images were obtained by Amersham Typhoon scanner (GE, US) overnight. The imaging data was analyzed by ImageQuant TL scanner (GE, US).

[0085] In vitro ARG on human brain sections with different diseases and normal control with different p-TDP43 loading demonstrated that lowest self-blocking effect was observed on normal human brain (30%) and 60-85% of self-blocking effects on disease brain sections. The highest blocking effect was found on brain sections from patient 15 (only showing TDP-43 pathology).

[0086] To measure the IC5o of [18F]-1 on frontal cortex sections from brain sections only showing TDP-43 pathology, an in vitro ARG IC5o assay was performed using the tracer. The results (see figure 3) show that the compound has a potency of 10 nM, which is close to its Kd value (7.9 nM) as measured by surface plasmon resonance assay.SURFACE PLASMON RESONANCE (SPR) MEASUREMENTS

[0087] Interactions between TDP43 aggregates and TDP43 compounds were analyzed using a Biacore S200 system (GE Healthcare, USA). An Anti Phospho-TDP43 (Ser409 / 410) antibody (Proteintech - USA) was immobilized at 100 ug / ml on a sensor chip (CM5: GE Healthcare) using an amine coupling agent (GE Healthcare). Cytoplasmic extracted samples from a brain containing TDP43 aggregates were injected as the analyte at 4 mg / ml and captured by the anti-phospho TDP43 antibody. TDP43 compounds were injected as samples (100- 0.39 nM series at 4-fold dilutions) into the HBS-EP+ running buffer (Cytiva, USA- 10 mM HEPES buffer [pH 7.4], 1.5 M NaCI, 0.03 M EDTA, 0.5% Surfactant P20) plus 5% DMSO. The binding / kinetics analysis was performed using the 1 :1 model. Data were corrected using a blank sensor chip as a control.

[0088] Binding activities and selectivity measurements of [18F]-1 and [18F]-3 show excellent selectivity over Ap (2,000x), PHF tau (900x) and a-syn (2,300x).The compounds [18F]-1 and [18F]-3 were found to bind differentially to TDP43 across brain pathologies obtained from different donors diagnosed with different neurodegenerative diseases.Additional compound data:IN VIVO PET IMAGING STUDIESIN IVO PET IMAGING STUDIES IN A MOUSE EXPRESSING HUMAN TDP-43

[0089] To investigate the binding of the18F-labeled PET ligand to TDP-43 in vivo, a mouse model induced by Adeno-Associated Virus 9 (AAV9) over expressing human TDP-43 was generated. AAV9-hSYN1-hTARDBP(A315T / G348C)-WPRE or AAV9-hSYN1-Null-WPRE (control) particles (3x1013GC / mL, genome copies per mL) were delivered to the frontal cortex of wild-type C57BL / 6J female mice via intracranial injections into the left hemisphere.

[0090] Four weeks post intracranial injections, animals were intravenously injected with ~150 pCi18F-labeled PET ligand. A 0-30-minute dynamic PET scan was performed followed by CT with GNEXT PET / CT scanner (Rolling Hills Estate, CA, US). The brain region was centered in the axial field of view (FOV) of the scanner (10 mm axial length) to maximize sensitivity and resolution. A similar procedure as imaging in rats was used to analyze the PET / CT mages. Both CT and PET images were reconstructed with the manufacturer’s software. Mouse Brain Atlas (Ma-Benveniste-Mirrione) in PMOD was used to calculate SUV values in different regions of the brain such as cortex.

[0091] In vivo PET imaging in this mouse model showed a good overlap of the [18F]-1 uptake on the left side of the cortex and phosphorylated TDP-43 detected with immunohistochemistry (Figure 5).IN VIVO PET IMAGING STUDIES IN NON-HUMAN PRIMATES (NHP)

[0092] The study was performed on a Focus-220 PET scanner focused on the brain.

[0093] A rhesus monkey was induced with Aflaxan® 2 mg / kg, dexmedetomidine 0.5 mg / kg, and midazolam 0.3 mg / kg intramuscularly (IM). Sedation was maintained with 1.25 - 1.75% isoflurane administered through a rebreathing circuit, along with Oxygen (1.2 - 1.5 L), to the end of the PET scan. The animal received Lactated Ringer’s Solution (LRS) plus 5% dextrose at 4-10 mL / kg / h IV. Body temperature was maintained at 36.9 - 37.8 °C using a heated water blanket.

[0094] Dynamic PET imaging was conducted for 0-240 min immediately following intravenous (IV) administration of ~5 mCi of18F-labeled PET ligand at baseline. PET images were normalized to a rhesus brain template to analyze different regions of the brain. Regions of interest, ROIs were defined based on atlas associated with the brain template.

[0095] Tracer time activity curves (TACs) were extracted from these regions of interest (ROI) and then normalized to SUV based on injected activity and animal weight. Standardized uptake value ratios (SUVR) were estimated to evaluate tracer selectivity. The PET data was then modelled with a two-tissue compartment (2TC) and with a one-tissue compartment (1TC) model to estimate distribution volume, VT(mL / cm3).

[0096] When evaluated in Rhesus macaque in a 240 min dynamic scan, [18F]-1 showed a higher SUV peak than rodents of 2.5 g / mL at ~ 9 min (~3.1 %ID), followed by a moderatewashout from the brain (whole brain %ID at 60 min & 240 min = 2.0% and 0.7%, respectively. The tracer metabolized with ~20%, and ~15% parent remaining at 30 min, and 180 min p.i., respectively. Only one more polar metabolite was detected in plasma. [18F]-1 shows low nonspecific binding and a moderate washout. The tracer readily enters the brain and displays reversible kinetics. MDCK-MDR1 assay indicates it is not a P- glyco protein (PGP) substrate.

Claims

AMENDED CLAIMS received by the International Bureau on 7 January 2026 (07.01.2026)1. A compound having Formula (I)or a stereoisomeric form thereof, whereinR1is [19F] or [18F];R2is selected from the group consisting of (a), (b), (c), (d) and (e)whereinX represents CR2aR2bor NR2c; wherein m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, CF3, CH2CHF2,Z represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; orSiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , of Formula (I’)whereinR1is [18F]R2is selected from the group consisting of (a), (b), (c), (d) and (e)whereinX represents CR2aR2bor NR2c; wherein m represents 1 or 2; n represents 0, 1 or 2;R2ais H, fluoro or methyl;R2bis selected from the group consisting of H, fluoro, methyl, ethyl, CHF2, CF3, CH2CHF2,Z represents SiR2dR2e, whereinR2dand R2eeach independently represent methyl or ethyl; or55SiR2dR2etogether formp is selected from the group consisting of 1 and 2; q is selected from the group consisting of 1 , 2 and 3;R3is hydrogen, fluoro or methoxy; or a pharmaceutically acceptable salt thereof.

3. A compound having the formulapharmaceutically acceptable salt thereof.

4. A compound having the formulaor a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

6. The pharmaceutical composition according to claim 5, wherein the composition is a sterile solution.

567. The pharmaceutical composition according to claim 5 or 6, wherein the compound is as defined in any one of claims 2 to 4.

8. Use of a compound of Formula as defined in any one of claims 2 to 4, or of a pharmaceutical composition as defined in claim 7, as an imaging agent.

9. The compound of any one of claims 2 to 4, or the pharmaceutical composition of claim 7, for use in diagnostic imaging of TDP-43 aggregates in the brain of a subject.

10. The compound or pharmaceutical composition for use in diagnostic imaging of claim 9, wherein the subject is a patient suffering from, or suspected to be suffering from, a TDP-43 related disorder or TDP-43 proteinopathy.

11. A method for imaging a tissue or a subject, comprising contacting with, or providing, or administering, a detectable amount of a radiolabelled compound as defined in any one of claims 2 to 4, to a tissue, or a subject, and detecting the radiolabelled compound.

12. The method according to claim 11, wherein the radiolabelled compound is detected by positron-emission tomography.

13. A method of using a radiolabelled compound of any one of claims 2 to 4, comprising introducing into a subject a detectable quantity of the radiolabelled compound, allowing sufficient time for the radiolabelled compound to bind to the TDP-43 aggregates and then detecting the radiolabelled compound in the brain of the subject.

14. The method according to claim 13 wherein the radiolabelled compound is detected using positron-emission tomography.

15. A process for the preparation of a compound of Formula (I’)57or a pharmaceutically acceptable salt thereof as defined in any one of claims 2 to 4, comprising the step of reacting a compound of Formula (P-l) with a source of [18F]fluoridewherein LG is a suitable leaving group, and R2and R3are as defined in Formula (I’) as defined in any one of claims 2 to 4; under suitable reaction conditions.

16. The process according to claim 15, for the preparation of the compound having the Formula ([18F]-1)comprising the step of reacting the compound (P-la’)with a source of [18F]fluoride, wherein LG is a leaving group selected from Cl and Br, in particular Cl; under suitable reaction conditions.

17. The process of claim 15, for the preparation of the compound having the Formula ([18F]-comprising the step of reacting the compound of Formula (P-l b’)source of [18F]fluoride, wherein LG is a leaving group selected from Cl and Br, in particular Cl; under suitable reaction conditions.

18. A compound of Formula (P-l)or a pharmaceutically acceptable salt thereof,wherein LG is a suitable leaving group, and R2and R3are each as defined in any one of claims 2 to 4.

19. A compound having the structurepharmaceutically acceptable salt thereof.

20. A compound having the structureor a pharmaceutically acceptable salt thereof.62

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