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WO1998001164A1 - Tricyclic radiolabeled d4 receptor ligands - Google Patents

Tricyclic radiolabeled d4 receptor ligands Download PDF

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Publication number
WO1998001164A1
WO1998001164A1 PCT/CA1997/000465 CA9700465W WO9801164A1 WO 1998001164 A1 WO1998001164 A1 WO 1998001164A1 CA 9700465 W CA9700465 W CA 9700465W WO 9801164 A1 WO9801164 A1 WO 9801164A1
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Prior art keywords
iodide
compound according
radioisotopic
tin
loweralkyl
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PCT/CA1997/000465
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French (fr)
Inventor
Alfred Pollak
Robert Dunn-Dufault
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Resolution Pharmaceuticals Inc.
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Priority to AU32509/97A priority Critical patent/AU3250997A/en
Publication of WO1998001164A1 publication Critical patent/WO1998001164A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D337/14—[b,f]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/14—[b,f]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention is in the field of medical diagnostics, and relates to radiolabeled compounds useful to image D4 receptor loci in brain tissue.
  • Neuronal cell receptors that bind the neurotransmitter dopamine constitute a group of at least five structurally distinct proteins that can now be produced using recombinant DNA techniques. These techniques have been applied to construct cell lines that incorporate the dopamine receptor in their membranes, to provide regenerable and homogeneous substrates with which chemical libraries can be screened to identify potential CNS-active drugs.
  • dopamine receptor ligands currently sold as pharmaceuticals exhibit the desired affinity and antagonism for the D4 receptor, yet interact non-selectively with related dopamine receptors, particularly the D2 receptor type, which results in significant side effects that include altered motor function and tachycardia.
  • this non-selective binding at the D4 receptor prevents the generation of an accurate image of the localisation and prevalence specifically of the D4 type of dopamine receptor. It would therefore be desirable to provide compounds that, in their radiolabeled state, bind at the D4 receptor with affinity and selectivity appropriate for diagnostic imaging purposes.
  • diagnostic imaging techniques as single photon emission tomography (SPECT)
  • SPECT single photon emission tomography
  • X -1' is selected from NH, O and S;
  • X 2 is selected from CH and N;
  • Z is selected from iodide, cyano, nitro, tri(loweralkyl)tin and a radioisotopic iodide; and R 1 is selected from H, lower alkyl, piperonyl, C ⁇ a-keny!, C M alkynyl and C M alkenyl substituted with one of iodide, tri(loweralkyl)tin and radioisotopic iodide; with the provisos that:
  • a radiopharmaceutical composition comprising the tricyclic compound of Formula I, selected from compounds wherein Z is a radioisotopic iodide and R 1 is C M alkenyl substituted with a radioisotopic iodide, and a pharmaceutically acceptable carrier, such as physiological buffered saline.
  • a method for imaging D4 receptors in vivo comprising the step of administering systemically to a patient an effective amount of the radiopharmaceutical composition, and then imaging the composition following its accumulation at D4 receptor sites in the brain.
  • lower alkyl refers to straight chain alkyl radicals containing from one to six carbon atoms, as well as branched chain alkyl radicals containing three to six carbon atoms; and includes methyl, ethyl, 1-methylethyl and the like.
  • C alkenyl refers to straight chain alkylene radicals containing from one to four carbon atoms, and branched chain alkylene radicals containing three to six carbon atoms; and includes vinyl, 2-propenyl and the like.
  • C ⁇ - 4 -dkynyl refers to straight chain alkynyl radicals containing from one to four carbon atoms, and branched chain alkylene radicals containing three to six carbon atoms; and includes propargyl, 2-propynyl and the like.
  • X and X are selected to provide a tricyclic ring structure which is a diazepine, an azepine, a thiazepine, a thiepine, an oxazepine or an oxepine.
  • the compound is a thiepine, i.e., X 1 is S and X 2 is
  • R 1 is desirably lower alkyl (for example methyl), a piperonyl group, C M alkenyl group or a ⁇ alkynyl group. In preferred embodiments, R 1 is selected from lower alkyl and piperonyl.
  • R 1 is a C M alkenyl group substituted with one of tri(loweralkyl)tin, iodide and radioisotopic iodide (including 123 I, 125 I and 131 I).
  • R 1 is 3- 123 I-2-propenyl.
  • Z is selected from cyano and a radioisotopic iodide including 123 I, l2S I and 131 I. In preferred embodiments, Z is selected from cyano and l23 I.
  • an appropriately substituted piperazine of Formula ⁇ is coupled with a tricyclic reagent of Formula HI, wherein X 3 is NH or CH 2 , in the presence of a Lewis acid, such as titanium tetrachloride or boron trifluoride-diethyl etherate, in an inert solvent at temperatures in the range of 100-150°C.
  • a Lewis acid such as titanium tetrachloride or boron trifluoride-diethyl etherate
  • Preferred conditions are titanium tetrachloride in toluene at 110°C.
  • the piperazines of Formula ⁇ can be obtained commercially or can be synthesized using well established procedures.
  • piperazine carboxaldehyde is treated with an alkylating reagent of the general formula, R'-X, wherein X is an appropriate leaving group such as chloride, bromide or iodide, in the presence of base, such as potassium carbonate or triethylamine, in an inert solvent such as acetone, acetonitrile or methylene chloride at temperatures in the range from 25-100°C.
  • base such as potassium carbonate or triethylamine
  • an inert solvent such as acetone, acetonitrile or methylene chloride
  • Preferred conditions are potassium carbonate in acetone at room temperature.
  • Removal of the carboxaldehyde protecting group can be accomplished using standard deprotection conditions (for example, aqueous sodium hydroxide at room temperature) to provide piperazines of Formula ⁇ .
  • Compounds of Formula I in which Z is limited to cyano or nitro and R 1 is a C alkenyl group substituted with tri(loweralkyl)tin, can be prepared by treating compounds of Formula I, wherein R 1 is a group, with a tri(loweralkyl)tin hydride under free radical conditions. Such reactions are performed, for example in the presence of an initiator, such as l,r-azobis(cyclohexanecarbonitrile), in an inert solvent, such as toluene, and at temperatures in the range from 50-110°C, preferably from 80-100°C.
  • an initiator such as l,r-azobis(cyclohexanecarbonitrile)
  • an inert solvent such as toluene
  • the starting tricyclic reagents of Formula in wherein X 1 is NH, O or S, X 3 is NH or CH 2 and Z is iodide, nitro or cyano, can either be purchased from commercial sources, or can be synthesized for example as described in numerous literature references, such as WO95/ 17400 published 29 June 1995.
  • Compounds of Formula I wherein R 1 is limited to lower alkyl, C M alkenyl, C 1 - 4 alkynyl or a piperonyl group and Z is tri(loweralkyl)tin can be prepared from compounds of Formula I, wherein Z is iodide, by reaction with hexa(loweralkyl)ditin reagents under standard palladium- catalysed cross coupling conditions.
  • Such conditions include, for example, treatment with hexa(loweralkyl)ditin reagents in the presence of a catalytic amount of tetra-ris(triphenylphosphine)palladium (0) in an inert solvent such as 1,2-dimethoxyethane at temperatures in the range from 50-100°C, preferably at about 80°C.
  • Compounds of Formula I in which either R 1 is a C M alkenyl group substituted with a radioisotopically labeled iodide or Z is a radioisotopically labeled iodide can be prepared, respectively, by reacting compounds of Formula I, in which either Z is tri(loweralkyl)tin or R 1 is a C M alkenyl group substituted with tri(loweralkyl)tin, with a solution of radioisotopically labeled sodium iodide (e.g. as a solution in IN NaOH) in the presence of an acid and hydrogen peroxide in an alcoholic solvent.
  • a solution of radioisotopically labeled sodium iodide e.g. as a solution in IN NaOH
  • Preferred conditions are hydrochloric acid in ethanol.
  • compounds of Formula I wherein R 1 is a C M alkenyl group substituted with a radioisotopically labeled iodide and Z is a radioisotopically labeled iodide can be prepared by reacting compounds of Formula I, wherein Z is tri(loweralkyl)tin and R 1 is a C alkenyl group substituted with tri(loweralkyl)tin.
  • Compounds of Formula I, wherein Z is iodide and R 1 is a C ⁇ a-keny! group substituted with iodide can be prepared by reacting compounds of Formula I, wherein Z is tri(loweralkyl)tin and R 1 is a C M alkenyl group substituted with tri(loweralkyl)tin, under standard iodination conditions, for example using iodine in an inert solvent such as chloroform at room temperature.
  • Compounds of Formula I wherein Z is tri(loweralkyl)tin and R 1 is a C M alkenyl group substituted with tri(loweralkyl)tin, can be prepared by reacting compounds wherein Z is iodide and R 1 is C 1 _ alkynyl under free radical conditions in the presence of a tri(loweralkyl)tin hydride and an initator as described above.
  • the compounds are selected from:
  • the compounds are selected from:
  • the compounds are selected from 2- 123 I-10-(4-methyl-l-piperazinyl)-dibenzo[b,flthiepine; 2- ,23 I -10-(4-piperonyl-l-piperazinyl)-dibenzo[b,f
  • the compounds of the invention are formulated as radiopharmaceutical compositions together with any physiologically and radiologically tolerable vehicle appropriate for administering the compound systemically. Included among such vehicles are phosphate buffered saline solutions, buffered for example to pH 7.4.
  • the present compounds will be administered to patients by intravenous injection or infusion at doses suitable (e.g. between 1 and 10 mCi) to generate an image of the compound as localised within the brain using for example a gamma camera. It is further contemplated that the method of the present invention can usefully be applied to patients suspected of suffering from schizophrenia. For these patients, diagnosis can be aided or confirmed by determining the intensity of radiolabeled compound relative to the brain of a healthy patient; greater image intensity is indicative of an overabundance of D4 receptor, and is hence indicative of a schizophrenic condition.
  • doses suitable e.g. between 1 and 10 mCi
  • the method of the present invention can usefully be applied to patients suspected of suffering from schizophrenia. For these patients, diagnosis can be aided or confirmed by determining the intensity of radiolabeled compound relative to the brain of a healthy patient; greater image intensity is indicative of an overabundance of D4 receptor, and is hence indicative of a schizophrenic condition.
  • 2-Chlorophenyl acetic acid (40.0 g, 0.235 mol) was dissolved in concentrated sulfiiric acid (200 mL) and the resulting solution cooled to -10°C with vigorous stirring. A solution of nitric acid (30 mL) and sulfiiric acid (30 mL) was then added dropwise over 1 hour and the thickened slurry was allowed to warm to 0°C. Ice water (500 mL) was then added, maintaining the temperature at 0°C. The solution was stirred and allowed to warm gradually to room temperature overnight. The resulting white solid was filtered, washed with copious amounts of water and dried over KOH in vacua. A pure sample of 2-chloro- 5-nitrophenyl acetic acid (44.35 g, 87.6%) was obtained by recrystallization in acetic acid.
  • Example 8(a) 2-Cvano- 10- ( 4-f3-( tributvltinV2- ⁇ ropen- l-vl "
  • Example 7a in dry dioxane (6 mL) under argon were added hexamethylditin (36 mg, 0.10 mmol) and tetrakis(triphenylphosphine)palladium (0) (10 mg, 0.092 mmol). The resulting solution was heated to 80°C for 2.5 hours and then cooled to room temperature, followed by the addition of water (8 mL). The product was extracted into dichloromethane (4x 2 mL) and the organics were combined, dried over sodium sulfate and concentrated. The resulting black oil was purified on a preparative silica gel plate using methanol/ethyl acetate (1:9) as eluent to provide the title compound as a yellow solid (20mg, 36.4%).
  • Example 11 2- (Radioisotopie-iodol- 10-f4-methyl- 1 -piperazinvD-dibenzorb . flthiepine
  • a solution of radioisotopically labeled sodium iodide (6 ⁇ L in 0.1 N NaOH) in ethanol (300 ⁇ L) is prepared in a reactivial and to this is added sequentially, the solution 2-trimethylstannyl-10- (4-methyl-l-piperazinyl)-dibenzo[b,f]thiepine, hydrochloric acid (0.3 N, 17 ⁇ L) and hydrogen peroxide (3%, 100 ⁇ L).
  • the resulting solution is swirled, adequately shielded and left stoppered for 15 minutes at room temperature.
  • D2 and D4 receptor-binding affinities of the compounds of Formula 1 were evaluated as described in WO95/ 17400 (incorporated herein by reference) for their ability to reduce binding of 3 H-spiperone as compared to the reference compound clozapine.
  • the potency of the test compound to reduce 3 H-spiperone binding directly correlated to its binding affinity for the receptor.
  • the D4 receptor was utilised in the form of membrane preparations obtained from HEK 298 cells stably transfected with human D4 receptor (D4.2 sub-type).
  • D2 receptor was utilised in the form of membrane preparations obtained from G ⁇ (rat pituitary) cells stably transfected with the human D2 receptor (short isofor ).
  • the total spiperone binding assay was started by the addition of 500 ⁇ l (50 ⁇ g protein) membrane homogenate to a solution of 900 ⁇ l incubation buffer and 100 ⁇ l (0.25 nM final cone.) 3 H-spiperone.
  • the binding reaction was stopped and the samples were filtered under vacuum and filters were then washed 3 times with 5 ml ice cold 50 mM Tris buffer (pH 7.4). Individual filter disks were put in scintillation vials (Biovials, Bechman). Ready Protein Plus liquid s nt ⁇ lant (5 ml, Beckman) was added and the vials counted by liquid scintillation spectrophotometry (Beckman LSC 6500) after equilibrating for three hours at room temperature to determine total binding ( ⁇ ).
  • Non-specific binding for D4 was assayed by incubating membrane homogenate, 3 H- spiperone and fresh dopamine. Filtrate was counted using the same procedure as in the total binding assay described above to give the non-specific binding value (NSB). Non-specific binding for D2 was similarly assessed, with the exception that (-) sulpiride was used in place of dopamine.
  • test compounds were initially assayed at 1 and 0.1 ⁇ M and then at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of 3 H- spiperone binding.
  • Specific binding in the absence of test compound (Bo) was the difference of total binding (B-) minus non-specific binding (NSB) and similarly specific binding (in the presence of test compound) (B) was the difference of displacement binding (Bo) minus non-specific binding (NSB).
  • IC 50 was determined from an inhibition response curve, logit-log plot of %B/B Q VS concentration of test compound.
  • Ki was calculated by the Cheng and Prustoff transformation:
  • Ki IC 50 / (l + [Lj7K D ) where [L] is the concentration of H-spiperone used in the assay and K D is the dissociation constant of 3 H-spiperone determined independently under the same binding conditions.

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Abstract

Herein described are radiolabeled compounds useful to image D4 receptors in vivo, of formula (I), wherein X1 is selected from NH, O and S; X2 is selected from CH and N; Z is selected from iodide, cyano, nitro, tri(loweralkyl)tin and a radioisotopic iodide; and R1 is selected from H, lower alkyl, piperonyl, C¿1-4?alkenyl, C1-4alkynyl and C1-4alkenyl substituted with one of iodide, tri(loweralkyl)tin and radioisotopic iodide; with the provisos that: (1) when one of Z and R?1¿ is radioisotopic, the other of Z and R1 is not or does not incorporate iodide; and (2) when one of Z and R1 is or incorporates tri(loweralkyl)tin, the other of Z and R1 is not or does not incorporate iodide or radioisotopically labeled iodide. The radiopharmaceutical compounds are useful particularly to image localisation of D4 receptor in the human brain, and can therefore aid in the diagnosis of schizophenia and other medical conditions in which the D4 receptor is implicated.

Description

TRICYCLIC RADIOLABELED D4 RECEPTOR UGANDS
This invention is in the field of medical diagnostics, and relates to radiolabeled compounds useful to image D4 receptor loci in brain tissue.
Background to the Invention
Neuronal cell receptors that bind the neurotransmitter dopamine constitute a group of at least five structurally distinct proteins that can now be produced using recombinant DNA techniques. These techniques have been applied to construct cell lines that incorporate the dopamine receptor in their membranes, to provide regenerable and homogeneous substrates with which chemical libraries can be screened to identify potential CNS-active drugs.
Recent evidence strongly implicates the dopamine receptor classified as D4 in the etiology of schizophrenia. It has been suggested that compounds capable of interfering with the function of this receptor, which is present in schizophrenics at levels that are six times normal, would be useful in the treatment of this disease (Seeman et al, Nature, 1993, 365:441). Therefore, it would be desirable to provide compounds that exhibit a high degree of affinity for the D4 receptor.
Some dopamine receptor ligands currently sold as pharmaceuticals exhibit the desired affinity and antagonism for the D4 receptor, yet interact non-selectively with related dopamine receptors, particularly the D2 receptor type, which results in significant side effects that include altered motor function and tachycardia. In the context of medical diagnostics, this non-selective binding at the D4 receptor prevents the generation of an accurate image of the localisation and prevalence specifically of the D4 type of dopamine receptor. It would therefore be desirable to provide compounds that, in their radiolabeled state, bind at the D4 receptor with affinity and selectivity appropriate for diagnostic imaging purposes. When used in combination with such diagnostic imaging techniques as single photon emission tomography (SPECT), such radiolabeled compounds would be useful particularly to diagnose schizophrenia and other medical conditions associated with D4 receptor anomalies.
Summary of the Invention
According to one aspect of the present invention, there are provided tricyclic compounds of Formula (I):
Figure imgf000004_0001
wherein
X -1' is selected from NH, O and S;
X2 is selected from CH and N;
Z is selected from iodide, cyano, nitro, tri(loweralkyl)tin and a radioisotopic iodide; and R1 is selected from H, lower alkyl, piperonyl, C^a-keny!, CMalkynyl and CMalkenyl substituted with one of iodide, tri(loweralkyl)tin and radioisotopic iodide; with the provisos that:
(1) when one of Z and R1 is radioisotopic, the other of Z and R1 is not or does not incorporate iodide; and (2) when one of Z and R1 is or incorporates -ri(loweralkyl)tin, the other of Z and R1 is not or does not incorporate iodide or radioisotopically labeled iodide.
According to another aspect of the invention, there is provided a radiopharmaceutical composition comprising the tricyclic compound of Formula I, selected from compounds wherein Z is a radioisotopic iodide and R1 is CMalkenyl substituted with a radioisotopic iodide, and a pharmaceutically acceptable carrier, such as physiological buffered saline.
In a further aspect of the invention, there is provided a method for imaging D4 receptors in vivo, comprising the step of administering systemically to a patient an effective amount of the radiopharmaceutical composition, and then imaging the composition following its accumulation at D4 receptor sites in the brain.
Detailed Description of the Invention
The term lower alkyl as used herein refers to straight chain alkyl radicals containing from one to six carbon atoms, as well as branched chain alkyl radicals containing three to six carbon atoms; and includes methyl, ethyl, 1-methylethyl and the like.
The term C alkenyl as used herein refers to straight chain alkylene radicals containing from one to four carbon atoms, and branched chain alkylene radicals containing three to six carbon atoms; and includes vinyl, 2-propenyl and the like.
The term Cι-4-dkynyl as used herein refers to straight chain alkynyl radicals containing from one to four carbon atoms, and branched chain alkylene radicals containing three to six carbon atoms; and includes propargyl, 2-propynyl and the like.
Compounds of the present invention are those of Formula I in which X1, X2, Z and R1 are as defined above. In embodiments of the invention, X and X are selected to provide a tricyclic ring structure which is a diazepine, an azepine, a thiazepine, a thiepine, an oxazepine or an oxepine. In a preferred embodiment, the compound is a thiepine, i.e., X1 is S and X2 is
CH. In another embodiment of the invention R1 is desirably lower alkyl (for example methyl), a piperonyl group, CMalkenyl group or a ^alkynyl group. In preferred embodiments, R1 is selected from lower alkyl and piperonyl.
In another embodiment of the invention R1 is a CMalkenyl group substituted with one of tri(loweralkyl)tin, iodide and radioisotopic iodide (including 123I, 125I and 131I). In a preferred embodiment, R1 is 3-123I-2-propenyl.
In another embodiment of the invention, Z is selected from cyano and a radioisotopic iodide including 123I, l2SI and 131I. In preferred embodiments, Z is selected from cyano and l23I.
To generate compounds of Formula I, wherein X1 and X2 are as defined above, Z is iodide, nitro or cyano and R1 is limited to lower alkyl,
Figure imgf000006_0001
CM-ilkynyl or a piperonyl group, an appropriately substituted piperazine of Formula π is coupled with a tricyclic reagent of Formula HI, wherein X3 is NH or CH2, in the presence of a Lewis acid, such as titanium tetrachloride or boron trifluoride-diethyl etherate, in an inert solvent at temperatures in the range of 100-150°C. Preferred conditions are titanium tetrachloride in toluene at 110°C.
Figure imgf000006_0002
II m
The piperazines of Formula π, wherein R1 is limited to lower alkyl, CMalkenyl, C^alkynyl or a piperonyl group, can be obtained commercially or can be synthesized using well established procedures. Thus, piperazine carboxaldehyde is treated with an alkylating reagent of the general formula, R'-X, wherein X is an appropriate leaving group such as chloride, bromide or iodide, in the presence of base, such as potassium carbonate or triethylamine, in an inert solvent such as acetone, acetonitrile or methylene chloride at temperatures in the range from 25-100°C. Preferred conditions are potassium carbonate in acetone at room temperature. Removal of the carboxaldehyde protecting group can be accomplished using standard deprotection conditions (for example, aqueous sodium hydroxide at room temperature) to provide piperazines of Formula π.
Compounds of Formula I, in which Z is limited to cyano or nitro and R1 is a C alkenyl group substituted with tri(loweralkyl)tin, can be prepared by treating compounds of Formula I, wherein R1 is a
Figure imgf000007_0001
group, with a tri(loweralkyl)tin hydride under free radical conditions. Such reactions are performed, for example in the presence of an initiator, such as l,r-azobis(cyclohexanecarbonitrile), in an inert solvent, such as toluene, and at temperatures in the range from 50-110°C, preferably from 80-100°C.
Compounds of Formula I in which Z is limited to cyano or nitro and R1 is a CMalkenyl group substituted with iodide are obtained from Formula I compounds in which R1 is a C|. 4alkenyl group substituted with tri(loweralkyl)tin by treatment thereof under standard iodination conditions, for example using iodine in an inert solvent such as chloroform at room temperature.
The starting tricyclic reagents of Formula in wherein X1 is NH, O or S, X3 is NH or CH2 and Z is iodide, nitro or cyano, can either be purchased from commercial sources, or can be synthesized for example as described in numerous literature references, such as WO95/ 17400 published 29 June 1995.
Compounds of Formula I, wherein R1 is limited to lower alkyl, CMalkenyl, C1-4alkynyl or a piperonyl group and Z is tri(loweralkyl)tin can be prepared from compounds of Formula I, wherein Z is iodide, by reaction with hexa(loweralkyl)ditin reagents under standard palladium- catalysed cross coupling conditions. Such conditions include, for example, treatment with hexa(loweralkyl)ditin reagents in the presence of a catalytic amount of tetra-ris(triphenylphosphine)palladium (0) in an inert solvent such as 1,2-dimethoxyethane at temperatures in the range from 50-100°C, preferably at about 80°C. Compounds of Formula I in which either R1 is a CMalkenyl group substituted with a radioisotopically labeled iodide or Z is a radioisotopically labeled iodide can be prepared, respectively, by reacting compounds of Formula I, in which either Z is tri(loweralkyl)tin or R1 is a CMalkenyl group substituted with tri(loweralkyl)tin, with a solution of radioisotopically labeled sodium iodide (e.g. as a solution in IN NaOH) in the presence of an acid and hydrogen peroxide in an alcoholic solvent. Preferred conditions are hydrochloric acid in ethanol. Using the same conditions, compounds of Formula I, wherein R1 is a CMalkenyl group substituted with a radioisotopically labeled iodide and Z is a radioisotopically labeled iodide can be prepared by reacting compounds of Formula I, wherein Z is tri(loweralkyl)tin and R1 is a C alkenyl group substituted with tri(loweralkyl)tin.
Compounds of Formula I, wherein Z is iodide and R1 is a C^a-keny! group substituted with iodide, can be prepared by reacting compounds of Formula I, wherein Z is tri(loweralkyl)tin and R1 is a CMalkenyl group substituted with tri(loweralkyl)tin, under standard iodination conditions, for example using iodine in an inert solvent such as chloroform at room temperature.
Compounds of Formula I, wherein Z is tri(loweralkyl)tin and R1 is a CMalkenyl group substituted with tri(loweralkyl)tin, can be prepared by reacting compounds wherein Z is iodide and R1 is C1_ alkynyl under free radical conditions in the presence of a tri(loweralkyl)tin hydride and an initator as described above.
In preferred embodiments of the invention, the compounds are selected from
2-iodo-10-(4-methyl-l-piperazmyl)-dibenzo[b,f]t-ύepine;
2-iodo-10-(4-ethyl-l-piperaz-nyl)-dibenzo[b,flthiepine;
2-iodo-l()-(4-propyl-l-piperazinyl)-dibenzo[b,f]thiepine; 2-iodo-10-(4-piperonyl-l-piperaz-nyl)-dibenzo[b,flthiepine; 2-(radioisotopic iodo)-10-(4-methyl-l-piperazinyl)-dibenzo[b,f] thiepine; 2-(radioisotopic iodo)- 10-(4-piperonyl-l-pipera--inyl)-dibenzo[b , fjthiepine; 2-cyano- 10-[4-(3-iodo-2-propen- 1 -yl)- 1 -piperaziny l]-dibenzo [b .fjthiepine; 2-cyano-10-(4-propargyl-l-piperazinyl)-dibenzo[b,f] thiepine; 2-cyano- 10- [4-(2-iodo-2-propen- 1 -yl)- 1 -piperaziny l]-dibenzo[b , f] thiepine;
2-cyano-10-{4-[3-(radioisotopic iodo)-2-propen-l-yl]-l-piperazinyl}-dibenzo[b, fjthiepine; and
2-cyano-l(^{4-[2-(radioisotopic iodo)-2-propen-l-yl]-l-piperazinyl}-dibenzo[b, fjthiepine.
In more preferred embodiments of the invention, the compounds are selected from
2-iodo- 10-(4-methyl- l-piperazinyl)-dibenzo[b,f|thiepine;
2-iodo-10-(4-piperonyl-l-piperazinyl)- libenzo[b,fl thiepine;
2-I123- 10-(4-methyl- l-piperazinyl)-dibenzo[b,f]thiq>ine;
2-I123-10-(4-piperonyl-l-pipera2inyl)-ώbenzo|^,f]thiepine; 2-cyanc-10-[4-(3-iodo-2-propen-l-yl)-l-piperazinyl]-dibenzo[b,f]thiepine; and
2-cyano- 10-[4-(3-123I -2-propen- 1 -yl)- 1 -piperazinyl]-dibenzo[b , fjthiepine.
In the most preferred embodiments of the invention, the compounds are selected from 2-123I-10-(4-methyl-l-piperazinyl)-dibenzo[b,flthiepine; 2-,23I -10-(4-piperonyl-l-piperazinyl)-dibenzo[b,f|thiepine; and
2-cyano- 10-[4-(3-123I -2-propen-l-yl)-l-piperazinylJ-dibenzo[b, fjthiepine.
The compounds of the invention are formulated as radiopharmaceutical compositions together with any physiologically and radiologically tolerable vehicle appropriate for administering the compound systemically. Included among such vehicles are phosphate buffered saline solutions, buffered for example to pH 7.4.
It is contemplated that the present compounds will be administered to patients by intravenous injection or infusion at doses suitable (e.g. between 1 and 10 mCi) to generate an image of the compound as localised within the brain using for example a gamma camera. It is further contemplated that the method of the present invention can usefully be applied to patients suspected of suffering from schizophrenia. For these patients, diagnosis can be aided or confirmed by determining the intensity of radiolabeled compound relative to the brain of a healthy patient; greater image intensity is indicative of an overabundance of D4 receptor, and is hence indicative of a schizophrenic condition.
Example 1: 2-Chloro-5-nitrophenvl acetic acid:
2-Chlorophenyl acetic acid (40.0 g, 0.235 mol) was dissolved in concentrated sulfiiric acid (200 mL) and the resulting solution cooled to -10°C with vigorous stirring. A solution of nitric acid (30 mL) and sulfiiric acid (30 mL) was then added dropwise over 1 hour and the thickened slurry was allowed to warm to 0°C. Ice water (500 mL) was then added, maintaining the temperature at 0°C. The solution was stirred and allowed to warm gradually to room temperature overnight. The resulting white solid was filtered, washed with copious amounts of water and dried over KOH in vacua. A pure sample of 2-chloro- 5-nitrophenyl acetic acid (44.35 g, 87.6%) was obtained by recrystallization in acetic acid.
Example 2: 2-Thiophenvl-5-nitrophenvl acetic acid:
To a solution of potassium hydroxide (10.94 g, 0.195 mol) in water (220 mL) purged with argon, was added thiophenol (11.25 g, 0.102 mol). After stirring for 10 minutes, 2-chloro-5-nitrophenyl acetic acid (20.0 g, 0.0928 mol, Example 1) was added followed by copper powder (1.18 g, 0.0186 mol) and the resulting solution was refluxed for 16 hours, followed by hot filtration and washing with hot water. The resulting filtrate was allowed to cool to room temperature and the product precipitated upon adjusting the pH to 4 using concentrated hydrochloric acid. This solid was filtered, washed with water and dried in vacuo to yield 2-thiophenyl-5-nitrophenyl acetic acid as a tan solid (22.8 g, 85%). Example 3: 2-Nitro-lO.l l-dihydrodibenzrb.flthiepin-lO-one:
To finely powdered 2-thiophenyl-5-nitrophenyl acetic acid (10.0 g, 0.0346 mol, Example 2) was added polyphosphoric acid (100 g). The resulting syrup was mixed manually to provide a homogeneous mixture and then heated to 120°C with occasional stirring. After 45 minutes, the reaction was cooled to 0°C and ice (600 mL) was added. The resulting solution was neutralized with sodium bicarbonate. Ethyl acetate was added and the solution filtered. The aqueous layer was extracted 3 times with a total volume of 500 mL of ethyl acetate. The organic layers were dried with sodium sulphate and evaporated to provide 2-nitro-10,ll-dihydrodibenz[b,f]thiepin-10-one (7.50 g, 80.2%) as a tan solid.
Example 4: 2-Amino-lO.l l-dihvdrodibenzrb.flthiepin-lQ-one:
To 2-nitro-10,ll-dihydrodibenz[b,f]thiepin-10-one (3.00 g, 11.06 mmol, Example
3) in 78% ethanol (lOOmL) was added a solution of calcium chloride (0.786 g, 7.08 mmol) in water (2 mL), followed by zinc powder (21.7 g, 332 mmol). The reaction was refluxed for 2 hours then it was filtered hot and washed with hot ethanol (100 mL). The solvents were removed to provide a sticky yellow solid. Water (30 mL) was added and the solid was allowed to precipitate overnight at 4°C. The yellow solid was filtered and washed with ice water (50 mL) and dried in vacuo to yield 2-amino-10,l l- dihydrodibenz[b,f]thiepin-10-one (2.56g, 96%).
Example 5(aY 2-Iodo-10.11-dihvdrodibenzn,.flthi-φ.n-10^ne*
To a stirred suspension of 2-amino-10,ll-dihydrodibenz[b,f]thiepin-10-one (3.00 g,
4.18 mmol, Example 4) in hydrochloric acid (50 mL, 2N) was slowly added a solution of sodium nitrite (0.948g, 13.7 mmol) in water (10 mL) at 0°C. After 10 minutes a solution of potassium iodide (2.60 g, 15.7 mmol) in water (10 mL) was slowly added with foaming and blackening of the reaction mixture. The ice bath was removed and the solution allowed to warm to room temperature. The reaction vessel was fitted with a condenser and heated to 55°C for 1 hour. After cooling to about 30°C, chloroform (150 mL) was added and the solution, filtered through a pad of celite. The organic layers were washed with sodium thiosulphate (50 mL) and dried over sodium sulphate. The product was purified by silica gel chromatography using hexanes.-ethyl acetate (7:1) to provide 2-iodo-10,l l- dihydrodibenz[b,f]thiepin-10-one (2.15 g, 49%) as a yellow crystalline solid; MS (ES): MH+ for C H9IOS calc'd 353, found 353.
In a like manner, the following additional compound was prepared: (b) 2-Cyano-10,ll-dihydrodibenz[b,f]thiepin-10-one, from copper (I) cyanide; yield: 14%.
xampte fr Propargylpiperazin-?
To a solution of potassium carbonate (36.3 g, 263 mmol) and piperazine carboxaldehyde (9.03 mL, 87.6mmol) in acetone (350 mL) was added, over 1 hour with stirring, a solution of propargyl bromide (13.68 g, 92 mmol) in acetone (75 mL) and the resulting mixture was stirred overnight. The resulting precipitate and excess potassium carbonate were filtered off and the organics concentrated to provide 4-propargyl piperazine carboxaldehyde (9.02g, 68%) as a yellow oil which solidified under high vacuum. This product (1.52 g, 10 mmol) was dissolved in water (85 mL) and sodium hydroxide (15 mL, 2N, 30mmol) was added and the resulting mixture was refluxed overnight. Sodium chloride (lOg) was then added and the solution extracted into dichloromethane (3x 120 mL). The organic layers were combined, dried over sodium sulfate and concentrated to provide the title compound as a yellow oil which crystallized under high vacuum (450 mg, 45%).
Example 7(aY. 2-Iodo-10-(4-methvl-l-piperazinvl dibenzorb.flthiepine
To a dry solution of 2-iodo-10,ll-dihydrodibenz[b,f]thiepin-10-one (50 mg, 0.142 mmol, Example 5a) in toluene (10 mL) under argon was added methylpiperazine (63 uL) followed by titanium tetrachloride (170 uL, 1M in toluene). The reaction mixture was refluxed for 16 hours and then allowed to cool to 60°C before isopropanol (1 mL), concentrated ammonium hydroxide (0.5mL) and celite were added. The slurry was filtered warm through a bed of celite and washed with ethyl acetate (10 L). The solvents were removed to provide a black oil. The product was purified by silica gel chromatography using ethyl acetate/hexanes (20%- 100%) as eluent to afford the title compound as yellow crystalline solid (42 mg, 68%); MS (ES): MH+ for C19H,9IN2S calc'd 435, found 435.
In a like manner, the following additional compounds were prepared:
(b) 2-Iodo-10-(4-piperonyl-l-piperazinyl)-dibenzo[b,f]thiepine, from piperonylpiperazine; yield: 52%; HRMS (FAB): MH+ calc'd for CHIN S 555.0603, found 555.0603.
(c) 2-Iodo-10-(4-ethyl-l-piperazinyl)-dibenzo[b, fjthiepine, from ethylpiperazine; yield: 47%; (d) 2-IodcHlO-(4-propyl-l-piperazinyl)-dibenzo[b,f|thiepine, from propylpiperazine; yield 54%;
(e) 2-Cyano-10-(4-propargyl-l-piperazinyl)-dibenzo[b,f]thiepine, from propargylpiperazine of Example 6 and 2-cyano-10,ll-dihydrodibenz[b,f|thiepin-10-one of Example 5(b); yield: 70%; HRMS (FAB): MH+ calc'd for C^H^S 358.1378, found 358.1380; and
(0 2-Nitro-10-(4-propargyl-l-piperazinyl)-dibenzo[b, fjthiepine, from propargylpiperazine and 2-nitro-10,ll-dihydrodibenz[b,flthiepin-10-one of Example 3.
Example 8(a) : 2-Cvano- 10- ( 4-f3-( tributvltinV2-ρropen- l-vl"|- 1 -piperazinyl}- dibenzorb.fi thiepine:
To a solution of 2-cyano- 10-(4-propargyl-l-piperazinyl)-dibenzo[b, fjthiepine (27 mg, 0.075 mmol, Example 7e) in anhydrous toluene (1.3 mL) were added 1,1'- azobis(cyclohexanecarbonitrile) (VAZO ) (4.6 mg, 0.019 mmol) and tributyltin hydride (65 μL, 0.242 mmol) and the resulting solution was heated to 80-100°C under argon for 3 hours. The reaction was allowed to cool to room temperature and concentrated. The product was purified by silica gel chromatography using ethyl acetate in hexanes (0-20%) as the eluent to provide the title compound as a waxy yellow oil (33 mg, 67%).
In a like manner, the following additional compound was prepared:
(b) 2-Cyano-10-{4-[2-(tributyltin)-2-propen-l-yl]-l-piperazinyl}-dibenzo[b, fjthiepine, isolated as a side product in Example 8(a); waxy yellow oil, yield: 13 mg, 27%.
Example 9(a.: 2-Cyano-10-r4-(3-iodo-2-propen-l-vlVl-piperazihvn-dibenzorb.f1thiepine
To a solution of 2-cyano-10-{4-[3-(tributyltin)-2-propen-l-yl]-l-piperazinyl}- dibenzofb, fjthiepine (49 mg, 0.0756 mmol, Example 8a) in chloroform, were added several aliquouts of a solution of iodine in chloroform (IM) until the color change persisted and the resulting solution was stirred at room temperature for 20 minutes. A solution of potassium fluoride in water (IM) was then added followed by a 5% aqueous solution of sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated. The product was purified by silica gel chromatography using ethyl acetate in hexanes (10-20%) as the eluent to provide the title compound as a yellow crystalline solid (14 mg, 38%); HRMS (FAB): MH+ calc'd for CJJHJO^S 486.0501, found 486.0483.
In a like manner, the following additional compound was prepared: (b) 2-Cyano-10-[4-(2-iod -2-propen-l-yl)-l-piperazinyl]-dibenzo[b,f]thiepine, from 2- cyano-10-{4-[2-(tributyltin)-2-propen-l-yl]-l-piperazinyl}-dibenzo[b,f]thiepine of Example 8(b); HRMS (FAB): MH+ calc'd for C22H2oIN3S 486.0501, found 486.0488.
Example 10: 2-Trimethvlstannvl- 10-(4-methvl- 1-piperazinylVdibenzorb.flthiepine
To a solution of 2-iodo-10-(4-methyl-l-piperazinyl)-dibenzo[b,f|thiepine (40 mg,
0.092 mmol, Example 7a) in dry dioxane (6 mL) under argon were added hexamethylditin (36 mg, 0.10 mmol) and tetrakis(triphenylphosphine)palladium (0) (10 mg, 0.092 mmol). The resulting solution was heated to 80°C for 2.5 hours and then cooled to room temperature, followed by the addition of water (8 mL). The product was extracted into dichloromethane (4x 2 mL) and the organics were combined, dried over sodium sulfate and concentrated. The resulting black oil was purified on a preparative silica gel plate using methanol/ethyl acetate (1:9) as eluent to provide the title compound as a yellow solid (20mg, 36.4%).
Example 11: 2- (Radioisotopie-iodol- 10-f4-methyl- 1 -piperazinvD-dibenzorb . flthiepine
A solution of 2-trimethylstannyl-10-(4-methyl-l -piperaziny l)-dibenzo[b, fjthiepine
(50-200 μg, Example 10) in dichloromethane (300 μL) is concentrated to an oil by passing argon over the solution through a septa in a 2 mL vial. Ethanol (300 μL) is then added and the resulting solution swirled to ensure complete dissolution. A solution of radioisotopically labeled sodium iodide (6 μL in 0.1 N NaOH) in ethanol (300 μL) is prepared in a reactivial and to this is added sequentially, the solution 2-trimethylstannyl-10- (4-methyl-l-piperazinyl)-dibenzo[b,f]thiepine, hydrochloric acid (0.3 N, 17 μL) and hydrogen peroxide (3%, 100 μL). The resulting solution is swirled, adequately shielded and left stoppered for 15 minutes at room temperature. After venting in the fumehood, aqueous solutions of sodium metabisulfite (150 mg/mL, 100 μL), sodium carbonate (saturated, 60 μL) and saline (100 μL) are added and the product extracted into dichloromethane (300 μL). The organic later is separated and analysed and purified by HPLC.
Example 12: Receptor Binding Affinities
D2 and D4 receptor-binding affinities of the compounds of Formula 1 were evaluated as described in WO95/ 17400 (incorporated herein by reference) for their ability to reduce binding of 3H-spiperone as compared to the reference compound clozapine. The potency of the test compound to reduce 3H-spiperone binding directly correlated to its binding affinity for the receptor.
Briefly, the D4 receptor was utilised in the form of membrane preparations obtained from HEK 298 cells stably transfected with human D4 receptor (D4.2 sub-type). D2 receptor was utilised in the form of membrane preparations obtained from Gϋ (rat pituitary) cells stably transfected with the human D2 receptor (short isofor ). The total spiperone binding assay was started by the addition of 500 μl (50 μg protein) membrane homogenate to a solution of 900 μl incubation buffer and 100 μl (0.25 nM final cone.) 3H-spiperone. The binding reaction was stopped and the samples were filtered under vacuum and filters were then washed 3 times with 5 ml ice cold 50 mM Tris buffer (pH 7.4). Individual filter disks were put in scintillation vials (Biovials, Bechman). Ready Protein Plus liquid s ntϋlant (5 ml, Beckman) was added and the vials counted by liquid scintillation spectrophotometry (Beckman LSC 6500) after equilibrating for three hours at room temperature to determine total binding ( γ).
Non-specific binding for D4 was assayed by incubating membrane homogenate, 3H- spiperone and fresh dopamine. Filtrate was counted using the same procedure as in the total binding assay described above to give the non-specific binding value (NSB). Non-specific binding for D2 was similarly assessed, with the exception that (-) sulpiride was used in place of dopamine.
To assess displacement, membrane homogenate was incubated with 3H-spiperone and test compound dissolved in DMSO. Filtrate was counted using the same procedure as in the total binding assay described above, to give the displacement binding value (Bo).
The test compounds were initially assayed at 1 and 0.1 μM and then at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of 3H- spiperone binding. Specific binding in the absence of test compound (Bo) was the difference of total binding (B-) minus non-specific binding (NSB) and similarly specific binding (in the presence of test compound) (B) was the difference of displacement binding (Bo) minus non- specific binding (NSB). IC50 was determined from an inhibition response curve, logit-log plot of %B/BQ VS concentration of test compound.
Ki was calculated by the Cheng and Prustoff transformation:
Ki= IC50 / (l + [Lj7KD) where [L] is the concentration of H-spiperone used in the assay and KD is the dissociation constant of 3H-spiperone determined independently under the same binding conditions.
Assay results (Ki) are reported in the following Table, and show clearly the D4 selectivity of compounds of the invention:
Compound D4(nM. D2(vM)
2-Iodo-10-(4-methyl-l-piperazinyl)-dibenzo[b,f]thiepine 8.0 58 2-Iodo-10-(4-piperonyl-l-piperazinyI)-dibenzo[b,fJthiepine 136 > 1000
2-cyano-10-[4-(3-iodo-2-propen-l-yl)-l-piperazinyl]- 163 241 dibenzo[b, fjthiepine

Claims

WE CLAIM:
1. A compound of Formula (I):
Figure imgf000018_0001
wherein
X1 is selected from NH, O and S; X2 is selected from CH and N;
Z is selected from iodide, cyano, nitro, tri(loweralkyl)tin and a radioisotopic iodide; and R1 is selected from H, lower alkyl, piperonyl, CMalkenyl, C,.4alkynyl and Cι-4-ϋkenyl substituted with one of iodide, txi(loweralkyl)tin and radioisotopic iodide; with the provisos that:
(1) when one of Z and R1 is radioisotopic, the other of Z and R1 is not or does not incorporate iodide; and
(2) when one of Z and R1 is or incorporates tri(loweralkyl)tin, the other of Z and Rl is not or does not incorporate iodide or radioisotopically labeled iodide.
2. A compound according to claim 1, wherein Z is selected from tri(loweralkyl)tin and radioisoptopic iodide and R1 is selected from H, lower alkyl, piperonyl, CMalkenyl and Cl- alkynyl.
3. A compound according to claim 2, wherein R1 is selected from lower alkyl and piperonyl.
4. A compound according to claim 3, wherein Z is radioisotopic iodide.
5. A compound according to claim 4, wherein Z is I.
6. A compound according to claim 2, wherein Xlis S and X2 is CH.
7. A compound according to claim 5, wherein X'is S and X2 is CH.
8. A compound according to claim 1, wherein Z is selected from cyano and nitro and R1 is CMalkenyl substituted with one of iodide, tri(loweralkyl)tin and radioisotopic iodide.
9. A compound according to claim 8, wherein Z is cyano and R1 is CM-tkenyl substituted with one of triQoweralkyl)tin and radioisotopic iodide.
10. A compound according to claim 9, wherein R1 is CMalkenyl substituted with 123I.
11. A compound according to claim 10, wherein x'is S and X2 is CH.
12. A compound according to claim 1, wherein Z is radioisotopic iodide and R1 is CMalkenyl substituted with radioisotopic iodide.
13. A compound according to claim 1 , wherein Z is iodide and R1 is C,^alkenyl substituted with iodide
14. A compound according to claim 1, selected from 2-123I-10-(4-memyl-l-piperazinyl)^ben--o|p,l]thiepine; 2-123I- 10-(4-piperonyl- l-piperazmyl)-dibenzo[b,fJthiepine; and 2-cyano-10-[4-(3-123I-2-propen-l-yl)-l-piperazinyl)-dibenzo[b,fJthiepine.
15. A radiopharmaceutical composition, comprising a radiopharmaceutically acceptable carrier and a compound as defined in claim 4 in an amount effective to image a human brain.
16. A radiopharmaceutical composition, comprising a radiopharmaceutically acceptable carrier and a compound as defined in claim 10 in an amount effective to image a human brain.
17. A radiopharmaceutical composition, comprising a radiopharmaceutically acceptable carrier and a compound as defined in claim 14 in an amount effective to image a human brain.
18. A method of radioimaging a human brain, comprising the step of administering systemically to a patient a radiopharmaceutical composition as defined in claim 15.
19. A method of radioimaging a human brain, comprising the step of administering systemically to a patient a radiopharmaceutical composition as defined in claim 16.
20. A method of radioimaging a human brain, comprising the step of administering systemically to a patient a radiopharmaceutical composition as defined in claim 17.
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