WO2009040377A2 - Imaging agents - Google Patents

Abstract

The invention relates to compounds of formula (I), or a salt or solvate thereof which comprise a detectable label. The compounds have use as radioligands for the GABAA receptor.

Description

IMAGING AGENTS

The present invention relates to the field of medical diagnostics and imaging, in one particular aspect to positron emission tomography (PET) and or single photon emission computed tomography (SPECT) and provides compounds and methods for visualising central nervous system (CNS) receptors. In particular, this invention relates to quinolines which are selective ligands for the GABA_A receptor and which carry a radiolabel suitable for imaging with PET or SPECT or a radiolabel suitable for localisation of GABA_A receptors in vitro. The compounds of the present invention are thus useful for /^'n vitro diagnostics and in vivo imaging of the GABA_A receptor

GABA (y -aminobutyric acid) is the most important inhibitory neurotransmitter in the human brain. Dysfunctions of GABAergic neurotransmission are implicated in many neurological and psychiatric disorders - for example, epilepsy and anxiety disorders, Parkinson's disease and chronic pain. Current evidence indicates that changes in the receptors which mediate GABAergic transmission are associated with particular CNS (central nervous system) disorders. GABA receptors fall into two main types - GABA_A and GABA₆ receptors. The development of new radioligands selective for GABA receptor subtypes will lead to major breakthroughs in terms of brain imaging studies in living human patients. At this stage the GABAA receptors are worthy of particular attention owing to the discovery of many GABA_A receptor subtypes and development of novel chemical structures which are selective for these subtypes. The field of GABA receptor imaging therefore appears to be poised at an exciting stage where development of radioligands for quantifying GABA receptor changes offer the potential to provide useful insight into numerous CNS disorders, such as those associated with epilepsy, anxiety and cognitive (neurodegenerative) disorders.

Certain quinolones are known GABA_A ligands, for example, Lager et al. J. Med. Chem. 2006, 2526-2533; and International patent application WO 00/68202.

- i - A number of compounds have been investigated as potential radioligands for studying the GABA_A receptor in vivo using PET including [¹¹C]flumazenil ([¹¹C]FMZ), [¹⁸F]fluoroflumazenil ([¹⁸F]FFMZ), [¹⁸F]fluoroethylflumazenil ([¹⁸F]FEFMZ), and [¹²³l]iomazenil ([¹²³I]IMZ). However, the majority of these compounds have suffered one or more disadvantages including short half-life, metabolic instability, and being difficult to prepare by radiochemical methods. The present invention seeks to provide radioligands suitable for studying the GABA_A receptor in vitro and in vivo having improved properties over those in the prior art.

According to the invention, there is provided a compound of formula (I):

or a salt or solvate thereof, wherein:

X is oxygen, sulphur, or NR¹⁰ wherein R¹⁰ is hydrogen or Ci_₆alkyl; R¹ is either:

(a) C_1-GaIkOXy, aryloxy, or arylC-ι_₆alkoxy each optionally substituted by 1 to 3 groups selected from halo, hydroxy, Ci_₆alkyl , C_1-6haloalkyl, Ci_-6alkoxy, Ci_ ehaloalkoxy, -NR¹¹R¹², and -C(O)OR¹¹ wherein R¹¹ and R¹² are each independently selected from hydrogen, Ci.βhaloalkyl and C_halky!; or

(b) NR¹³R¹⁴ wherein R¹³ and R¹⁴ are independently selected from hydrogen, hydroxy, C_halky!, aryl, arylCi_₆alkyl and are each optionally substituted by a group selected from halo, hydroxy, C_1-4alkyl, -C(O)NR¹⁵R¹⁶ , -C(O)OR¹⁵ wherein R¹⁵ and R¹⁶ are each independently selected from hydrogen, Ci_-6alkyl and Ci_₆ haloalkyl or wherein R¹³ and R¹⁴ together with the nitrogen to which they are bonded form a 5-, 6-, or 7-membered nitrogen containing ring optionally substituted by one or two groups selected from those described as optional substituents for R¹³ and R¹⁴; or (c) C_halky!, aryl, or a ry I C i_ ₆a Iky I each optionally substituted by 1 to 3 groups selected from halo, hydroxy, Ci_-6alkyl , Ci_-6haloalkyl, Ci_-6alkoxy, Ci_-6haloalkoxy, -NR¹⁷R¹⁸, and -C(O)OR¹⁷ wherein R¹⁷ and R¹⁸ are each independently selected from hydrogen, Ci_₆haloalkyl and Ci_₆alkyl;

R², R³, R⁴, R⁵, and R⁶ are each independently selected from hydrogen, halo, nitro, Ci-₆alkyl, Ci_-6haloalkyl, hydroxy, Ci_-6alkoxy, C-i_₆haloalkoxy, aryl, arylCi_-6alkyl, aryloxy, arylC_1-6alkoxy, cyano, thiocyanate, -NR¹⁹R²⁰, -NR¹⁹C(O)R²⁰ , -SR¹⁹, -SO₂NR¹⁹R²⁰ , -C(O)R¹⁹ and -C(O)OR¹⁹ wherein R¹⁹ and R²⁰ are each independently selected from hydrogen, C-i-βhaloalkyl, C_halky!, aryl, and arylC-i. ₆alkyl and wherein any aryl groups in R², R³, R⁴, R⁵, and R⁶ are optionally substituted by 1 to 3 groups selected from halo, hydroxy, C_halky! , Ci_₆haloalkyl, Ci-₆alkoxy, -NR²¹R²², and -C(O)OR²¹ wherein R²¹ and R²² are each independently selected from hydrogen C_1-6alkyl and d-βhaloalkyl;

R⁷ is selected from hydrogen, Ci_-6alkyl, C_1-6 haloalkyl, -CO₂H, Ci_₆ haloalkoxycarbonyl and Ci_₆alkoxycarbonyl;

and wherein at least one of -C(X)R¹ or R² to R⁷ comprises a detectable label; provided that the compound of formula (I) is not ethyl 7-chloro-1-ethyl-[1 -¹⁴C]-6- fluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylate.

In a compound of formula (I), and in following aspects of the invention:

X is suitably oxygen or sulphur, and is preferably oxygen;

R¹ is preferably either:

(a) Ci_₆alkoxy or C-ι-6 haloalkoxy; or (b) NR¹³R¹⁴ wherein R¹³ and R¹⁴ are independently selected from hydrogen,

Ci-βalkyl, aryl, and arylCi_₆alkyl and are each optionally substituted by a group selected from halo, hydroxy, and Ci_₄alkyl; Compounds of formula (I) in which R¹ is C_halky!, aryl, or arylCi_₆alkyl each optionally substituted by 1 to 3 groups selected from halo, hydroxy, C_halky! , C-ι.₆haloalkyl, Ci_-6alkoxy, Ci.ehaloalkoxy, -NR¹⁷R¹⁸, and -C(O)OR¹⁷ wherein R¹⁷ and R¹⁸ are each independently selected from hydrogen, Ci_-6haloalkyl and C-ι_₆alkyl form a separate aspect of the invention;

Compounds of formula (I) in which R¹ is C-i-βalkoxy, aryloxy, orarylC-ι-₆alkoxy each optionally substituted by 1 to 3 groups selected from halo, hydroxy, Ci_-6alkyl , Ci_-6haloalkyl, C_1-6alkoxy, Ci_-6haloalkoxy, -NR¹¹R¹², and -C(O)OR¹¹ wherein R¹¹ and R¹² are each independently selected from hydrogen, C_1-6haloalkyl and C-ι.₆alkyl form a separate aspect of the invention;

Compounds of formula (I) in which R¹ is NR¹³R¹⁴ wherein R¹³ and R¹⁴ are independently selected from hydrogen, hydroxy, C_halky!, aryl, aryl C_halky I and are each optionally substituted by a group selected from halo, hydroxy, C-ι_-4alkyl, -

C(O)NR¹⁵R¹⁶ , -C(O)OR¹⁵ wherein R¹⁵ and R¹⁶ are each independently selected from hydrogen, C_halky! and Ci-₆haloalkyl or wherein R¹³ and R¹⁴ together with the nitrogen to which they are bonded form a 5-, 6-, or 7-membered nitrogen containing ring optionally substituted by one or two groups selected from those described as optional substituents for R¹³ and R¹⁴ form a separate aspect of the invention;

R², R³, R⁴, R⁵, and R⁶ are preferably each independently selected from hydrogen, halo, nitro, Ci_₆alkyl, Ci-₆haloalkyl, hydroxy, Ci_₆alkoxy, and Ci_₆haloalkoxy ; suitably R², R³, R⁵, R⁶ are each hydrogen, and R⁴ is selected from halo, nitro, Ci-₆alkyl, C-i.βhaloalkyl, hydroxy, Cvβalkoxy, d-δhaloalkoxy, aryl, and aryl C_halky!; R² is preferably hydrogen;

R⁷ is preferably selected from hydrogen, C_halky!, and C-ι_₆ haloalkyl, and is more preferably hydrogen; Compounds of formula (I) in which R², R³, R⁵, R⁶ are each hydrogen, and R⁴ is benzyl form a separate aspect of the invention.

Suitable detectable labels in a compound of formula (I) and in more specific aspects of the invention below include a radiolabel suitable for imaging with PET or SPECT such as ¹³¹- ¹²³' ^{124> 122}I, ⁷⁵Br, ⁷⁶Br₁ ⁷⁷Br, ¹³N, ¹¹C, or ¹⁸F, or a radiolabel suitable for localisation of GABA_A receptors in vitro or in vivo such as ³H, ¹⁴C, ³⁵S, or ¹²⁵I. In one aspect of the invention, the detectable label is a radiolabel suitable for imaging with PET or SPECT, suitably selected from ¹³¹- ¹²³' ¹²⁴' ¹²²I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹³N, ¹¹C, and ¹⁸F, and is preferably ¹⁸F. In an alternative aspect of the invention, the detectable label is a radiolabel suitable for localisation of GABA_A receptors in vitro, suitably selected from such as ³H, ¹⁴C, ³⁵S, or ¹²⁵I.

The detectable label is comprised in one or more of groups -C(X)R¹ or R² to R⁷, for example where the detectable label is ¹³¹- ¹²³- ¹²⁴' ¹²⁵' ¹²²1, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, or ¹⁸F it may be incorporated where one or more of groups -C(X)R¹ or R² to R⁷comphses halo and where the detectable label is ¹¹C, it may be incorporated where one or more of groups -C(X)R¹ or R² to R⁷ comprises carbon. Suitably, one of the groups -C(X)R¹, or R² to R⁶comprises the detectable label, more suitably - C(X)R¹, R⁴ , or R⁵comprises the detectable label. In one aspect of the invention, the detectable label is comprised in group -C(X)R¹ . In a further aspect of the invention, the detectable label is comprised in group R⁴.

When the detectable label is a radiohalo i.e. ^{131 > 123}' ¹²⁴' ¹²⁵' ¹²²1, ⁷⁵Br, ⁷⁶Br₁ ⁷⁷Br, or ¹⁸F, it may be directly bonded to the rest of the compound of formula (I).

Alternatively radiohalo radiolabels are commonly incorporated as radiohaloCi. ₆alkyl groups such as [¹⁸F]fluoroethyl or [¹⁸F]fluoropropyl, or radiohaloC-ι_₆alkoxy groups such as [ Fjfluoroethoxy or [ Fjfluoromethoxy. [ C]carbon radiolabels are commonly incorporated as [¹¹C] C^a Iky I groups such as [¹¹C]methyl or [¹¹C]ethyl or as a [¹¹C]carbonyl group.

Thus, in a preferred aspect of the invention, there is provided a compound of formula (Ia):

or a salt or solvate thereof, wherein:

R¹ is either:

(a) Ci_₆alkoxy or Ci_-6 haloalkoxy; or

(b) NR¹³R¹⁴ wherein R¹³ and R¹⁴ are independently selected from hydrogen, Ci- ₆alkyl, aryl, and arylCi_₆alkyl and are each optionally substituted by a group selected from halo, hydroxy, and Ci_-4alkyl;

R², R³, R⁴, R⁵, and R⁶ are each independently selected from hydrogen, halo, nitro, d-βalkyl, Ci_-6haloalkyl, hydroxy, Ci_₆alkoxy, and Ci_₆haloalkoxy ; suitably R², R³, R⁵, R⁶ are each hydrogen, and R⁴ is selected from halo, nitro, Ci_-6alkyl, Ci- βhaloalkyl, hydroxy, Ci_-6alkoxy, Ci_₆haloalkoxy, aryl, and aryl C_halky!; and

R⁷ is selected from hydrogen, Ci_-6alkyl, and Ci_-6 haloalkyl;

and wherein at least one of -C(X)R¹ or R² to R⁷ comprises a detectable label; provided that the compound of formula (Ia) is not ethyl 7-chloro-1 -ethyl-[1 -¹⁴C]-6- fluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylate.

Particular compounds of formula (I) include 6-ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[ 18r F]fluoro-ethyl)-amide;

6-benzyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[ 18r F]fluoro-ethyl)-amide;

6-bromo-4-oxo-1 ^-dihydro-quinoline-S-carboxylic acid (2-[ 18 Fr ]fluoro-ethyl)-amide;

6-ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[ 18r F]fluoro-propyl)-amide; 6-benzyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-amide; 6-bromo-4-oxo-1 ^-dihydro-quinoline-S-carboxylic acid (3-[¹⁸F]fluoro-propyl)-amide; 6-ethyl-4-oxo-1 ^-dihydro-quinoline-S-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-ester; 6-bromo-4-oxo-1 ^-dihydro-quinoline-δ-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-ester; 6-ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-ester; 6-bromo-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-ester;

Λ ft

6-benzyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[ F]fluoro-ethyl)-N- methyl-amide;

6-benzyl-3-((S)-3-[¹⁸F]fluoro pyrrolidine-1 -carbonyl)-1 H-quinoline-4-one; 7-fluoro-4-oxo-1 ^-dihydro-quinoline-S-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide; 6-iodo-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide; 6-(2-[¹⁸F]fluoroethyl)-4-oxo-1 ^-dihydro-quinoline-δ-carboxylic acid (3-propyl)- amide; 6-(2-[¹⁸F]fluoroethyl)-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester;

or a salt or solvate of any thereof .

Preferred compounds of formula (I) include

6-ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide; 6-benzyl-4-oxo-1 ^-dihydro-quinoline-S-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide;

6-bromo-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide;

6-benzyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-amide;

6-bromo-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-amide;

6-benzyl-3-((S)-3-[¹⁸F]fluoro pyrrolidine-1 -carbonyl)-1 H-quinoline-4-one; 7-fluoro-4-oxo-1 ^-dihydro-quinoline-S-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide;

6-iodo-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide;

6-(2-[¹⁸F]fluoroethyl)-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-propyl)- amide;

6-(2-[¹⁸F]fluoroethyl)-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester;

or a salt or solvate of any thereof . Suitable salts according to the invention include (i) physiologically acceptable acid addition salts such as those derived from mineral acids, for example hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and those derived from organic acids, for example tartaric, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic, methanesulphonic, and para- toluenesulphonic acids; and (ιι) physiologically acceptable base salts such as ammonium salts, alkali metal salts (for example those of sodium and potassium), alkaline earth metal salts (for example those of calcium and magnesium), salts with organic bases such as triethanolamine, N-methyl-D-glucamine, piperidine, pyridine, piperazine, and morpholine, and salts with amino acids such as arginine and lysine

Suitable solvates according to the invention include those formed with ethanol, water, saline, physiological buffer and glycol.

As used herein the term "halo" either alone or as part of another term means iodo, bromo, chloro, or fluoro.

As used herein the term "alkyl" either alone or as part of another term means a straight, branched or cyclic alkyl group.

As used herein the term "aryl" either alone or as part of another term means a carbocyclic aromatic system, suitable examples being phenyl or naphthyl, more suitably phenyl.

As demonstrated below, the compounds of formula (I) and (Ia) have use as radioligands for the GABA_A receptor Therefore, according to a further aspect of the invention, there is provided a compound of formula (I) or (Ia) as defined above, or a salt or solvate thereof wherein the detectable label is a radiolabel suitable for imaging with PET or SPECT suitably selected from ^{131 123 124 122}I₁ ⁷⁵Br₁ ⁷⁶Br₁ ⁷⁷Br,

N, C, and F, and is preferably F₁ for use in an in vivo diagnostic or imaging method such as PET or SPECT Suitably, a compound of formula (I) or (Ia) as defined above, or a salt or solvate thereof may also be used to image the GABA_A receptor in healthy human volunteers for example for clinical research purposes.

Suitably, the compounds of formula (I) or (Ia) or salt or solvate thereof wherein the detectable label is a radiolabel suitable for imaging with PET or SPECT suitably selected from ¹³¹' ¹²³' ¹²⁴' ¹²²1, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹³N, ¹¹C, and ¹⁸F, and is preferably ¹⁸F are useful for in vivo imaging of GABA_A receptors and thus provide information and data having utility in the diagnosis and clinical research of GABA_A- mediated disorders.

The term "GABA_A-mediated disorders" means neurological and neuropsychiatric disorders such as stroke, epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, sleep disorders, alcoholism , and neuropathic pain. One important GABA_A-mediated disorder is epilepsy and in particular post-traumatic epilepsy.

Accordingly, there is further provided use of a compound of formula (I) or (Ia) or a salt or solvate thereof in the manufacture of a radiopharmaceutical for the in vivo diagnosis or imaging of a GABA_A-mediated disorder. In the alternative, there is provided a compound of formula (I) or (Ia) or a salt or solvate thereof for use in the in vivo diagnosis or imaging of a GABA_A-mediated disorder.

In a further aspect, there is provided a method for the in vivo diagnosis or imaging of GABA_A- mediated disorder in a subject, preferably a human, comprising administration of a compound of formula (I) or (Ia) or a salt or solvate thereof wherein the detectable label is a radiolabel suitable for imaging with PET or SPECT suitably selected from ¹³¹- ¹²³- ¹²⁴' ¹²²1, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹³N, ¹¹C, and ¹⁸F, and is preferably F and detecting the uptake of said compound by an in vivo imaging technique such as SPECT or PET. The method is especially preferred for the in vivo diagnosis or imaging of stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and neuropathic pain, especially epilepsy and in particular post-traumatic epilepsy. In one aspect of the invention, the method comprises detecting the uptake of a compound of formula (I) or (Ia) or a salt or solvate thereof wherein the detectable label is a radiolabel suitable for imaging with PET or SPECT suitably selected from ^{131 123 124 122}1, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹³N, ¹¹C, and ¹⁸F, and is preferably ¹⁸F by an in vivo imaging technique such as SPECT or PET in a subject, preferably a human to whom said compound has been pre-administered

The invention further provides a method of monitoring the effect of treatment of a subject, preferably a human with a drug to combat a GABA_A- mediated disorder, said method comprising administering to said subject a compound of formula (I) or (Ia) or a salt or solvate thereof and detecting the uptake of said compound by an in vivo imaging technique such as SPECT or PET, said administration and detection optionally but preferably being effected repeatedly, e g before, during and after treatment with said drug

A compound of formula (I) or (Ia) or a salt thereof is preferably administered for //? vivo use in a radiopharmaceutical formulation comprising the compound of the invention and a pharmaceutically acceptable excipient A "radiopharmaceutical formulation" is defined in the present invention as a formulation comprising compound of formula (I) or (Ia) or a salt thereof in a form suitable for administration to humans Administration is preferably carried out by injection of the formulation as an aqueous solution Such a formulation may optionally contain further ingredients such as buffers, pharmaceutically acceptable solubilisers (e g cyclodextπns or surfactants such as Pluronic, Tween or phospholipids), pharmaceutically acceptable stabilisers or antioxidants (such as ascorbic acid, gentisic acid or para-aminobenzoic acid)

The effective in vivo dose of a compound of formula (I), (Ia) or a salt thereof vary depending on the exact compound to be administered, the weight of the patient, and other variables as would be apparent to a physician skilled in the art Generally, the dose would lie in the range 0 001 μg/kg to 10 μg /kg, preferably 0 01 μg /kg to 1 0 μg/kg As mentioned above, the compounds of formula (I), (Ia) and salts thereof may also have use in the field of in vitro diagnostics for localisation of GABA_A receptors in vitro. In this aspect of the invention, the detectable label in the compound of formula (I), (Ia) or a salt thereof is suitably ³H, ¹⁴C, ³⁵S, or ¹²⁵I. GABA_A may be

5 localised in biopsy or post-mortem tissue by incubating the tissue with a solution comprising a compound of formula (I), (Ia) or a salt thereof. The solution is suitably aqueous, or an aqueous organic solvent mix such as aqueous ethanol.

Upon incubation the compound of formula (I), (Ia) or a salt thereof labels the

GABA_A receptor in the tissue and may be detected by any standard technique, for i o example by autoradiography, or gamma counter. Therefore, in a further aspect of the invention, there is provided a method for localisation of GABA_A receptors in biopsy or post-mortem tissue which comprises incubating said tissue with a solution comprising a compound of formula (I), (Ia) or a salt thereof wherein the detectable label is suitably ³H, ¹⁴C, ³⁵S, or ¹²⁵I and then detecting the labelled

15 deposits.

Compounds of formula (I) wherein the group R¹C(X)- is an ester or amide and R¹ comprises a detectable label may be prepared from the corresponding compound of formula (II):

or a protected derivative thereof, wherein X and R² to R⁷ are as defined for the compound of formula (I) by reaction with the appropriate alcohol or amine compound of formula (III): 5

R¹-H (III)

wherein R¹ is as defined for the compound of formula (I) and comprises a detectable label. The reaction of a compound of formula (II) with a compound of formula (III) may be effected by any standard esterification or amidation method. Suitably the compound of formula (II) is converted to the corresponding activated ester, for example to an acid chloride by reaction with oxalyl chloride or to a pentafluorophenyl ester before addition of the compound of formula (III) in the presence of a base, such as a trialkylamine, for example diisopropylethylamine or triethylamine.

Compounds of formula (I) wherein the group R¹C(X)- is a ketone and R¹ comprises a detectable label may be prepared from an ester of the corresponding compound of formula (II) as defined above by reduction of the group -COOR^a, wherein R^a is a C-ι-₆alkyl, aryl, or aryl C_halky! group, using a suitable reducing agent, for example, Diisobutylaluminium hydride to provide the corresponding aldehyde, followed by reaction with the appropriate Grignard Reagent of formula (IV):

BrMg-R¹ (IV)

wherein R¹ is as defined forthe compound of formula (I) or is a precursor therefor, such as a hydroxyalkyl or tosylalkyl group which can be subsequently reacted with fluoride. Coupling of a compound of formula (II) with a compound of formula (IV) may be effected using standard methods such as those described in March's

Advanced Organic Chemistry (5^th Ed., Michael B Smith and Jerry March, John

Wiley and Sons Inc.) which also describes subsequent hydrolysis and oxidation steps to form the desired ketone. An example of synthesis of a compound of formula (I) in which -C(X)R¹ is a ketone is given in scheme 1 in which R² to R⁷ are as defined above, DIBAL-H is diisobutylaluminium hydride.

Scheme 1

Mg

BrMg^_^/\^,OBn Dess Martin Reagent

Tosyl chloride DCM TEA

KF Kryptofix

Acetonitπle

Compounds of formula (II) are either commercially available or may be prepared by methods such as those described in Lager et al, J Med. Chem. (2006), 49, 2526-2533, or WO 00/68202. Compounds of formula (III) may be prepared by radiohalogenation, radiohaloalkylation, or [¹¹C]alkylation methods, such as those described in Lasne et a/, Topics in Current Chemistry, VoI 222, pp201 -256 and M.J Welch and CS Redvanly, Handbook of Radiopharmaceuticals, Radiochemistry and Applications (Wiley, 2003) using a corresponding precursor amine or alcohol, suitably wherein the amine or hydroxyl group is protected as described below.

Compounds of formula (IV) may be prepared by conventional methods, such as those described in March's Advanced Organic Chemistry (5^th Ed., Michael B Smith and Jerry March, John Wiley and Sons Inc.)

Alternatively, compounds of formula (I) wherein the group R¹C(X)- is an amide and R¹ comprises a detectable label may be prepared according to Scheme 2 or by methods analogous thereto, in which DABCO is 1 ,4-diazabicyclo[2.2.2]octane, and R² to R⁶ are as defined above. Scheme 2

~ O

, Ph DABCO, toluene _C-A- NaOH₁ CH₃OH SH . — — ^- o O I

P I BH, 40 degrees L^ *^" ^pph, Ph - PPh, ²

As would be appreciated by a person skilled in the art, protecting groups may be required during synthesis of a compound of formula (I) to prevent unwanted side- reactions. Therefore, protected derivatives of synthetic intermediates such as a compound of formula (II) comprise one or more protecting groups to prevent unwanted reaction of certain reactive groups. Suitable protecting groups may be found in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc. which describes methods for incorporating and removing such protecting groups.

¹⁸F may be incorporated into a compound of the invention either by nucleophilic or electrophilic fluorination methods. The fluorine may be incorporated directly, for example, by nucleophilic displacement of a leaving group by [¹⁸F]fluoride, or by way of a ¹⁸F-fluohnated labelling agent which is prepared and then attached to the target molecule by a second reaction, such as an alkylation.

[¹⁸F]fluoride is conveniently prepared from ¹⁸O-enriched water using the (p,n)- nuclear reaction, (Guillaume ef a/, Appl. Radiat. Isot. 42 (1991 ) 749-762) and generally isolated as the potassium salt which is dried and solubilised with a phase transfer agent such as a tetraalkylammonium salt or an aminopolyether (for example, Kryptofix 2.2.2). Nucleophilic displacement of a leaving group, often a sulphonate ester, such as a p-toluenesulphonate, trifluoromethanesulphonate, or methanesulphonate, nitro, thCi_₄alkylammonium group, or a halo group such as iodo or bromo, may typically be effected by heating for 10 to 30 minutes at elevated temperatures, for example 80 to 160⁰C, suitably 60 to 120^°C, or by microwave heating, in a polar aprotic solvent such as acetonitrile, dimethylsulphoxide, or dimethylformamide.

Useful [¹⁸F]labelling agents include the [¹⁸F]fluoroalkylhalides, such as [¹⁸F]fluoropropylbromide. These are routinely prepared by nucleophilic displacement of a suitable leaving group by [ Fjfluoride before being coupled to a suitable precursor.

Electrophilic [¹⁸F]fluorination may be performed using ¹⁸F₂, alternatively the ¹⁸F₂ may be converted to [¹⁸F]acetylhypofluorite (Lerman et a/, Appl. Radiat. Isot. 49 (1984), 806-813) or to a N-[18F]fluoropyridinium salt (Oberdorfer et al, Appl. Radiat. Isot. 39 (1988), 806-813). These electrophilic reagents may be used to incorporate ¹⁸F by performing double bond addition, aromatic substitution reactions, for example substitution of a trialkyl tin or mercury group, or fluorination of carbanions.

Compounds of formula (I) wherein one of the groups R² to R⁶ comprises a detectable label may be prepared by conventional radiolabelling techniques, such as aromatic nucleophilic [¹⁸F]fluorination involving displacement of a nitro, iodonium, or tetraalkylammonium group, or by radioiodide or radiobromide displacement of a trialkyltin precursor, such as a tributylstannyl precursor, in the presence of an oxidising agent such as peracetic acid, N-chlorosuccinimide, and N-chlorotolylsulphonamide (for example chloramine-T or iodogen), at non- extreme temperature and in a suitable solvent such as an aqueous buffer. Radiohalogenation methods are reviewed in detail in Bolton, J Label. Compd Radiopharm 2002, 45, 485-528.

A thorough review of ¹¹C-labelling techniques, suitable for incorporation of a ¹¹C detectable label may be found in Antoni et al "Aspects on the the Synthesis of ¹¹C- Labelled Compounds" in Handbook of Radiopharmaceuticals, Ed. MJ. Welch and CS. Redvanly (2003, John Wiley and Sons).

Certain compounds of formula (I) wherein the group R¹C(X)- is an ester or amide and R⁴ comprises a detectable label may be prepared according to Scheme 3 or by methods analogous thereto, wherein R is ethoxy or propylamino, Boc is t- butoxycarbonyl, TBDMS is te/t-butyldimethylsilyl, and Et is ethyl. Scheme 3

R

Tosyl chloride tπethylamine dichloromethane

Compounds of formula (I) wherein R⁷ comprises a detectable label may be prepared by radiohalogenation, radiohaloalkylation, or [¹¹C]alkylation reactions such as those described in Lasne et al, Topics in Current Chemistry, VoI 222, pp201-256 and M.J Welch and CS Redvanly, Handbook of Radiopharmaceuticals, Radiochemistry and Applications (Wiley, 2003).

According to a further aspect of the invention there is provided a kit for the preparation of a radiopharmaceutical formulation, said kit comprising a compound of formula (II) as defined above. In use of the kit, the compound of formula (II) would be converted to the corresponding compound of formula (I) by reaction with a compound of formula (III) using the process described above.

The invention will now be illustrated by way of the Examples in which the following abbreviations are used:

TLC : thin layer chromatography NMR : nuclear magnetic resonance DIBAL-H: Diisobutylaluminum hydride DMSO : dimethyl sulphoxide

DCM : dichloromethane

HPLC : high performance liquid chromatography

HATU : O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DIPEA : Diisopropylethylamine TEA : Triethylamine DMF : N,N-dimethyl formamide rt : room temperature eq : equivalent(s) LCMS : liquid chromatography mass spectroscopy

Et : ethyl Bn : benzyl All the intermediates were characterised by NMR and LCMS when required. Final compounds were characterised by NMR, LCMS and HPLC to check the purity (above 95% required for in vitro screening)

Preparation of Intermediates 4a, 4b, 4c

diphcm lcthci i cflux

4a.b

Preparation of Intermediate 3b. 4-benzylaniline (Aldrich, 5g, 0.0273moles, 1 eq) and diethyl ethoxymethylenemalonate (Aldrich 5.5ml, 0.0273moles, 1 eq) were mixed in a round bottom flask. The mixture was heated for about 3 hours at 12O⁰C before reaction went to completion. (TLC hexane/ethylacetate, 7:3). Ethanol formed in the reaction was removed in vacuo. The crude was characterised by ¹H-NMR confirming the desired structure. The compound was used for the next step without purification.

Preparation of Intermediates 3a and 3c.

These were prepared by methods analogous to those described for Intermediate 3b from ethyl aniline (Aldrich) and bromoaniline (Aldrich) respectively. Preparation of Intermediate 4b

Intermediate 3b (9 6g, 0 0273moles) was dissolved in 15 ml of diphenyl ether and the reaction mixture was refluxed for about 1 hour The mixture was allowed to cool and a precipitate formed Petroleum ether was added to allow more product to precipitate The precipitate was collected by filtration and washed with petrol to remove traces of diphenyl ether The fine powder was then left under vacuum before NMR characterisation

Preparation of Intermediate 4a

By methods analogous to those described for Compound 4b, using Intermediate 3a

Preparation of Intermediate 4c

Intermediate 3c (330mg, 0 879mmoles) was transferred into a microwave vessel and dissolved in 2 ml of diphenylether The experiment was run at 25O⁰C for 5 minutes Then, petroleum ether was added and the precipitate formed was collected by filtration ¹H-NMR confirmed the structure of the desired compound obtained in quantitative yield

Preparation of Intermediates 5a, 5b, and 5c

4a-c 5a-c

Preparation of Intermediate 5b

Compound 4b (1 34g, 4 4mmoles, 1 eq) was dissolved in ethanol 5 ml of NaOH 2M solution (1 Ommoles, 2 2eq) were added The reaction mixture was refluxed for 2 hours, until the starting material was not visible anymore on TLC (ethyl acetate) The ethanol was evaporated and the solid residue left was collected by filtration and washed with ethyl acetate The compound was then left in the oven at 8O⁰C under vacuum over night, before ¹H-NMR was run

Intermediate 5a and 5c were prepared by analogous methods from Intermediate 4a and 4c respectively

Example 1 : Synthesis of Compounds 6a, 6b, 6c, 7b and 7c.

6a 6-ethyl-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (2-fluoro-ethyl)-amιde 6b 6-benzyl-4-oxo-1 ,4-dιhydro-quιnohne-3-carboxylιc acid (2-fluoro-ethyl)-amιde 6c 6-bromo-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (2-fluoro-ethyl)-amιde 7b 6-benzyl-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (3-fluoro-propyl)-amιde 7c 6-bromo-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (3-fluoro-propyl)-amιde

HATU. DIPEA, DMF rt. fluoroethylamine/fluoropropylamine

Preparation of Compound 6b.

Intermediate 5b (294mg, 1.06mmoles, 1 eq) was dissolved in 10 ml of DMF. HATU (443mg, 1.166mmoles, 1.1 eq) was then added, followed by addition of fluoroethylamine hydrochloride (158mg, 1.59mmoles, 1.5eq) previously dissolved in DMF in the presence of DIPEA (554μl, 3.18mmoles, 3eq). The reaction mixture was left stirring overnight at room temperature (TLC: ethylacetate/methanol, 95:5). The DMF was evaporated to dryness and the reaction crude was dry loaded on column for flash chromatography using 0-5% methanol in ethylacetate. The desired compound was isolated as a white solid analysed by ¹H-NMR and LCMS.

6b. ¹H-NMR (CD₃OD) δ (ppm): 3.70 (1 H, t, J-5.2 Hz), 3.79 (1 H, t, J=5.2 Hz), 4.13 (2H, s), 4.50 (1 H, t, J-4.90 Hz), 4.64 (1 H, t, J=4.90 Hz), 7.15-7.31 (5H,m), 7.56 (1 H, d, J-8.27 Hz), 7.61 (1 H, dd, J-8.28, 1.55 Hz), 8.20 (1 H, d, J= 1.53 Hz), 8.74 (1 H₁ S).

Preparation of compounds 6a, 6c, 7b, and 7c was achieved by methods analogous to those described for compound 6b. 6a. ¹H-NMR (CD₃OD) δ (ppm): 1.30 (3H, t, J-7.66 Hz), 2.81 (2H, q, J-7.35 Hz), 3.70 (1 H, t, J=4.90 Hz), 3.79 (1 H, t, J=4.90 Hz), 4.51 (1 H, t, J=4.90), 4.66 (1 H, t,

J=4.90 Hz), 7.55 (1 H, d, J=8.58 Hz), 7.65 (1 H, d, J=8.58 Hz), 8.17 (1 H, s), 8.74

(1 H₁ S).

6c. ¹H-NMR (CD₃OD) δ (ppm): 3.70 (1 H, t, J=4.90 Hz), 3.79 (1 H, t, J=4.60 Hz),

4.50 (1 H, t, J=5.21 Hz), 4.66 (1 H, t, J=5.21 Hz), 7.56 (1 H, d, J=8.89 Hz), 7.84 (1 H, dd, J=2.14, 8.89 Hz), 8.46 (1 H, d, J=2.14 Hz), 8.80 (1 H, s).

7b. ¹H-NMR (CD₃OD) δ (ppm): 1.91-2.10 (2H, m), 3.57 (2H, t, J=6.74 Hz), 4.13

(2H, s), 4.47 (1 H, t, J=5.82 Hz), 4.63 (1 H, t, J=5.82 Hz), 7.15-7.30 (5H,m), 7.56

(1 H, d, J=8.58 Hz), 7.61 (1 H, d, J=8.58 Hz), 8.19 (1 H, s), 8.73 (1 H, s).

7c. ¹H-NMR (CD₃OD) δ (ppm): 1.91 -2.10 (2H, m), 3.57 (2H, t, J=6.43 Hz), 4.49

(1 H, t, J=5.82 Hz), 4.63 (1 H, t, J=5.82 Hz), 7.56 (1 H, d, J=8.89 Hz), 7.84 (1 H, d,

J=8.89 Hz), 8.45 (1 H, s), 8.75 (1 H, s).

Example 2 : Synthesis of Compound 8 8 6-benzyl-3-((S)-3-fluoro pyrrolidiπe-1-carbonyl)-1 H-quinoline-4-one

5b

Intermediate 5b (294mg, 1.06mmoles, 1 eq) was dissolved in 10 ml of DCM. Oxalyl chloride (93μl, 1.Oδmmoles, 1 eq) was then added. The reaction was stirred until generation of gas was completed and left stirring for 10 minutes further, followed by addition of S-3-fluoropyrrolindine hydrochloride (200mg, 1.59mmoles, 1.5eq) previously dissolved in DCM in the presence of DIPEA (554μl, 3.18mmoles, 3eq). The reaction mixture was left stirring overnight at room temperature (TLC: ethylacetate/methanol, 95:5). The DCM was evaporated to dryness and the reaction crude was dry loaded on column for flash chromatography using 0-5% methanol in ethylacetate over a time of 19.0 CV on the companion. The desired compound was isolated as a white solid analysed by ¹H-NMR and LCMS. 8. ¹H-NMR (CD₃OD) δ (ppm) 2 02-2 32 (2H, m), 3 52-3 96 (4H, m), 4 10 (2H, s), 5 29 (1 H, m) 7 13-7 31 (5H, m), 7 51 (1 H, d, J= 8 58 Hz), 7 58 (1 H, d, J= 8 58 Hz), 8 10-8 16 (2H, m)

Example 3 : Synthesis of Compound 11

11 7-fluoro-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (2-fluoro-ethyl)-amιde

c d

11

Preparation of compound 9 This compound was prepared by analogous method to compound 4c

Preparation of compound 10 This compound was prepared by analogous method to compound 5a

Preparation of compound 11 This compound was prepared by analogous method to compound 8

Compound 11 ¹H-NMR ((CD₃)₂SO) δ (ppm) 3 62 (1 H, t, J=5 21 Hz), 3 70 (1 H, t,

J=5 21 Hz), 4 47 (1 H, t, J=4 90 Hz), 4 62 (1 H, t, J=4 90 Hz), 7 33 (1 H, m, J=2 45,

5 52 Hz), 7 45 (1 H, dd, J= 2 45, 9 50 Hz), 8 29 (1 H, dd, J= 5 82, 9 50 Hz), 8 70

(1 H, s)

Example 4 : Synthesis of Compound 14

14 6-ιodo-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (2-fluoro-ethyl)-amιde

12 13

Compound 13 was prepared by analogous method to compound 4a-c. Compound 14 was prepared by analogous method to Compound 8. Compound 14 ¹H-NMR ((CD₃)₂SO) δ (ppm): 3.65 (2H, dq, J_HF=27 Hz, J_HH=10 Hz, J_HH=6 HZ₁), 4.55 (2H, dt, J_HF=47 HZ, J_HH=5 HZ), 7.53 (1 H, d, J_HH=9 Hz), 8.05 (1 H, dd, J_HH=9 HZ, J_HH=2 HZ), 8.53 (1 H, s, ArCH), 8.77 (1 H, d, J_HH=1 HZ), 10.1 (1 H, br t, J=6 Hz).

Compounds 6a, 6b, 6c, 7b, 7c, 11 , and 14 may be prepared with a detectable label by using the appropriately labelled alcohol or amine in the final step of the synthesis or using the radiolabelling methods described more generally above.

[¹⁸F] fluoride was transferred to a 3 ml_ Wheaton vial , the P6 vial was rinsed with a solution of Kryptofix 222 (5 mg, 1.34^χ10^~5 mol in 500 μL acetonitrile and 50μL of

0.1 M potassium carbonate) and transferred to the Wheaton vial. The solution was dried at 100⁰C under a flow of N₂ (0.3L/ minute) for 20 minutes, then cooled to room temperature.

To the dried [¹⁸F]fluoride was added toluenesulfonic acid-2-azidoethyl ester

(2μL) in acetonitrile (0.2ml_), the Wheaton vial sealed and heated to 80⁰C for 20mιnutes, when the temperature was increased to 130⁰C and the [¹⁸F]fluoroethylazιde was allowed to distil, via a short length of tubing, into 1 mL Wheaton vial which was chilled in ice

To compound 15, prepared as described generally above (2mg, 4><10 mol) in a mixture of 10% water in DMF (100μL) was added the [¹⁸F]fluoroethylazιde in acetonitπle (~0 2ml_) The reaction mixture was heated at 130⁰C for 15 minutes, when it was allowed to cool to room temperature Water (1 OOμL) was added and the resulting colourless precipitate was removed by filtration (0 45μm, PALL ACRODISK™ CR13) to give the crude product The reaction mixture was diluted into water (3m L) and was purified by preparative HPLC

The HPLC purified sample was diluted into water (3OmL) and reformulated using a tC18 light SPE cartridge

Biological Examples

To determine in vitro affinities of the compounds, a standard radioligand binding assay for rat GABA_A receptor was used Membranes (ex vivo rat cerebellar membranes, 500ng/ml) were incubated with [³H] flumazenil (1 8nM) (PerkinElmer) in the presence or absence of a range of test compound concentrations Nonspecific binding was performed in presence of excess diazepam (Sigma) (1 OμM) Final assay volume was 10Oμl) Assay wells were incubated at room temperature for 1 hour and the assay terminated by filtration Bound radioactivity was detected using a scintillation counter

The compounds of the Examples, when tested in this screen gave an Ki of below 1 OnM

Claims

Claims

1. A compound of formula (I):

or a salt or solvate thereof, wherein:

X is oxygen, sulphur, or NR¹⁰ wherein R¹⁰ is hydrogen or Ci-₆alkyl;

R¹ is either:

(a) Ci_₆alkoxy, aryloxy, or arylC-i-βalkoxy each optionally substituted by 1 to 3 groups selected from halo, hydroxy, C_halky! , Ci-βhaloalkyl, Ci_₆alkoxy, Ci- ehaloalkoxy, -NR¹¹R¹², and -C(O)OR¹¹ wherein R¹¹ and R¹² are each independently selected from hydrogen, d_₆haloalkyl and Ci_₆alkyl; or

(b) NR¹³R¹⁴ wherein R¹³ and R¹⁴ are independently selected from hydrogen, hydroxy, Ci_₆alkyl, aryl, arylCi.₆alkyl and are each optionally substituted by a group selected from halo, hydroxy, C_1-4alkyl, -C(O)NR¹⁵R¹⁶ , -C(O)OR¹⁵ wherein R¹⁵ and R¹⁶ are each independently selected from hydrogen, C-i_₆alkyl and Ci-₆ haloalkyl or wherein R¹³ and R¹⁴ together with the nitrogen to which they are bonded form a 5-, 6-, or 7-membered nitrogen containing ring optionally substituted by one or two groups selected from those described as optional substituents for R¹³ and R¹⁴; or

(c) C-ι-₆alkyl, aryl, or aryl C_halky I each optionally substituted by 1 to 3 groups selected from halo, hydroxy, d^alkyl , Ci_-6haloalkyl, C-i_-6alkoxy, Ci_-6haloalkoxy, -NR¹⁷R¹⁸, and -C(O)OR¹⁷ wherein R¹⁷ and R¹⁸ are each independently selected from hydrogen, Ci_₆haloalkyl and d-βalkyl;

R², R³, R⁴, R⁵, and R⁶ are each independently selected from hydrogen, halo, nitro, Ci_₆alkyl, Ci-_θhaloalkyl, hydroxy, Ci_₆alkoxy, Ci_₆haloalkoxy, aryl, arylCi-βalkyl, aryloxy, arylC-i-βalkoxy, cyano, thiocyanate, -NR 19_π R20 -NR¹⁹C(O)R²⁰ , -SR¹⁹, -SO₂NR¹⁹R²⁰ -C(O)R¹⁹ and -C(O)OR¹⁹ wherein R¹⁹ and R²⁰ are each independently selected from hydrogen, Ci_-6haloalkyl, Ci_₆alkyl, aryl, and arylC-i. ₆alkyl and wherein any aryl groups in R², R³, R⁴, R⁵, and R⁶ are optionally substituted by 1 to 3 groups selected from halo, hydroxy, Ci_₆alkyl , Ci_-6haloalkyl, CCii__₆₆aallkkooxxyy,, --NNRR²²¹¹RR²²²²,, aanndd --CC((OO))OORR²²¹¹ wwhheerreeiinn RR²²¹¹ aannd R²² are each independently selected from hydrogen C_halky! and Ci_-6haloalkyl;

R⁷ is selected from hydrogen, Ci_-6alkyl, C_1-6 haloalkyl, -CO₂H, Ci_-6 haloalkoxycarbonyl and Ci_-6alkoxycarbonyl;

1 o y and wherein at least one Of -C(X)R or R to R comprises a detectable label; provided that the compound of formula (I) is not ethyl 7-chloro-1 -ethyl-[1 -¹⁴C]-6- fluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylate.

2. A compound of formula (Ia):

or a salt or solvate thereof, wherein: R¹ is either:

(a) Ci.₆alkoxy or Ci_-6 haloalkoxy; or

(b) NR¹³R¹⁴ wherein R¹³ and R¹⁴ are independently selected from hydrogen, Ci- ealkyl, aryl, and

and are each optionally substituted by a group selected from halo, hydroxy, and Ci_-4alkyl;

R², R³, R⁴, R⁵, and R⁶ are each independently selected from hydrogen, halo, nitro, Ci_-6alkyl, Ci_-6haloalkyl, hydroxy, Ci_-6alkoxy, and Ci_-6haloalkoxy ; suitably R², R³, R⁵, R⁶ are each hydrogen, and R⁴ is selected from halo, nitro, Ci_-6alkyl, Ci- βhaloalkyl, hydroxy, Ci^alkoxy, C-i-ehaloalkoxy, aryl, and arylCi_₆alkyl; and

R⁷ is selected from hydrogen, C_halky!, and C-i-β haloalkyl;

5 and wherein at least one of -C(X)R¹ or R² to R⁷ comprises a detectable label; provided that the compound of formula (Ia) is not ethyl 7-chloro-1 -ethyl-[1 -¹⁴C]-6- fluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylate.

3. A compound according to claim 1 or 2 wherein the detectable label is ao radiolabel suitable for imaging with PET or SPECT such as ¹³¹- ¹²³' ¹²⁴' ¹²²I, ⁷⁵Br, 7⁶Br₁ ⁷⁷Br, ¹³N, ¹¹C, or ¹⁸F, or a radiolabel suitable for localisation of GABA_A receptors in vitro or in vivo such as ³H, ¹⁴C, ³⁵S, or ¹²⁵I.

4. A compound according to any of claims 1 to 3 wherein R⁷ is hydrogen. 5

5. A compound according to any of claims 1 to 4 wherein the detectable label is a radiolabel suitable for imaging with PET or SPECT such as ¹³¹' ¹²³' ¹²⁴' ¹²²I, ⁷⁵Br, 7⁶Br₁ ⁷⁷Br, ¹³N, ¹¹C₁ or ¹⁸F₁ and is preferably ¹⁸F.

0 6. A compound according to any one of claims 1 to 5 selected from:

6-ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide; 6-benzyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide; 6-bromo-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide; 6-ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-amide; 5 6-benzyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-amide;

6-bromo-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-amide; 6-ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-ester; 6-bromo-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-ester; 6-ethyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-[¹⁸F]fluoro-propyl)-ester; o 6-bromo-4-oxo-1 ^-dihydro-quinoline-S-carboxylic acid (3-[¹⁸F]fluoro-propyl)-ester;

6-benzyl-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-N- methyl-amide;

6-benzyl-3-((S)-3-[¹⁸F]fluoro pyrrolidine-1 -carbonyl)-1 H-quinoline-4-one;

7-fluoro-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (2-[¹⁸F]fluoro-ethyl)-amide;

Λ 9K

6-iodo-4-oxo-1 ,4-dihydro-quiπoline-3-carboxylic acid (2-[ F]fluoro-ethyl)-amide;

6-(2-[¹⁸F]fluoroethyl)-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid (3-propyl)- amide;

6-(2-[¹⁸F]fluoroethyl)-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid ethyl ester;

or a salt or solvate of any thereof .

7. A compound according to claim 5 or 6 for use in an in vivo diagnostic or imaging method such as PET or SPECT.

8. A compound according to claim 5 or 6 or a salt or solvate thereof for use in the in vivo diagnosis or imaging of a GABA_A-mediated disorder.

9. A radiopharmaceutical formulation comprising the compound as defined in claim 5 or 6 and a pharmaceutically acceptable excipient.

10. A method for the in vivo diagnosis or imaging of GABA_A- mediated disorder in a subject, preferably a human, comprising administration of a compound of formula (I) or (Ia) as defined in claim 5 or 6 or a salt or solvate thereof and detecting the uptake of said compound by an in vivo imaging technique such as SPECT or PET.

11. A process for preparation of a compound of formula (I) or (Ia) as defined in any one of claims 1 to 6 or a salt or solvate thereof, which comprises reaction of a compound of formula (II):

or a protected derivative thereof, wherein X and R² to R⁷ are as defined for the compound of formula (I) by reaction with the appropriate alcohol or amine compound of formula (III):

R¹-H (III)

wherein R , 1 is as defined for the compound of formula (I) and comprises a detectable label.

12. A kit for the preparation of a radiopharmaceutical formulation comprising a compound of formula (II) as defined in claim 1 1.