HETEROCYCLIC COMPOUNDS AS IMAGING PROBES OF TAU PATHOLOGY
Technical Field of the Invention
The present invention relates to radiolabeled quinoline and isoquinoline compounds,
compositions thereof, methods of making such compounds and their use as imaging
probes of Tau pathology especially as it relates to Alzheimer' s Disease. Compounds of
the present invention may be used for Positron Emission Tomography (PET) or Single
Photon Emission Computed Tomography (SPECT) imaging.
Description of Related Art
Alzheimer' s disease (AD) is the most common cause of dementia in the elderly. It is
definitively diagnosed and staged on the basis of post-mortem neuropathology. The
pathological hallmark of AD is a substantial neuronal loss accompanied by deposition
of amyloid plaques and neurofibrillary tangles (NFTs).
NFTs consist of filamentous aggregates composed of microtubule-associated protein
tau. Much of the literature suggests that tau aggregates (NFTs) or NFT formation
correlate more closely with AD progression than amyloid plaques (Braak, H. et a ,
Neuropathological Staging of Alzheimer-related Changes. Acta Neuropathologica, 82,
239-259, 1991). The tau aggregates or neurofibrillary lesions reportedly appear in areas
(deep temporal lobe) decades before neocortical amyloid deposition and signs of
dementia can be detected. The tau lesions occur before the presentation of clinical
symptoms or signs of dementia and correlate with the severity of dementia. These
attributes make tau aggregates a potentially superior approach for the early diagnosis of
AD. Hence in vivo detection of these lesions or NFTs would prove useful for diagnosis
of AD and for tracking disease progression.
One of the challenges in discovering NFT imaging probes is the selectivity for other
protein aggregates (such as amyloid plaques) containing a cross beta-sheet
conformation. Kudo et al. have recently screened compounds for selectivity toaggregated tau over amyloid in vitro. BF-170 and BF-158 were described as being
-threefold selective for tau aggregates over ΑβΙ -42 amyloid:
BF-1 70 BF-1 58
Ec5 (tau) = 221 nM Ec5 (tau) = 399 nM
Ec50 (amyloid) = 786 nM EC50(amyloid) = 659 nM
(Kudo, Y., et al, J. Neuroscience, 2005, 25(47): 10857-10862). These compounds and
other quinoline derivatives are also described in US 2005/0009865, now US 7,1 18,730,
as diagnostic probes for the imaging diagnosis of diseases in which tau protein
accumulates. The probes can be labeled with a radionuclide.
However there still exist a need in the art for compounds that can be used as imaging
agents for NFTs. The present invention described below answers such a need.
Summary of the Invention
The present invention provides novel quinoline compounds for use as imaging
probes of Tau pathology in Alzheimer's disease. The compounds of the inventions may
be radiolabeled such that they may be used for in vitro and in vivo imaging purposes.
The present invention provides a compound of Formula I :
wherein:
Ri is independently H, halogen, OH, COOH, S0 3H, NH2, N0 2, CONHNH2, alkyl, or
alkoxy;
R2 is independently H, halogen, OH, COOH, S0 3H, NH2, N0 2, CONHNH2, alkyl, oralkoxy;
R4 is independently H or NR5R 6 where R and R are each independently H, alkyl,
haloalkyl, -(CH2)qOR7, -(CH2)qO(CH2) OR7, -(CH )qNR7R , -(CH ) aryl, -
(CH2)qheteroaryl, -(CH2)qheterocyclyl, where R and R may be further optionally
substituted with at least one group selected from the group consisting of -OH, -OR 3,
N(R3)2, C(0)OR 3, C(0)N(R 3)2, S0 2N(R3)2where R3 is independently H, alkyl, aryl,
heteroaryl, heterocyclyl, cycloalkyl, wherein R3 is further optionally substituted; or R
and R taken together taken together with the nitrogen to which they are attached form a
cyclic or aromatic moiety which optionally contains at least one other heteroatom
selected from the group consisting of nitrogen, oxygen and sulfur and which is
optionally substituted with at least one of halogen, OH, COOH, S0 H, NH2, N0 2,
CONHNH2, alkyl, or alkoxy;
R7 and R are each independently H, alkyl, -(CH2)
t
NR R io or R 7 and R taken together
with the nitrogen to which they are attached form a cyclic or aromatic moiety which
optionally contains at least one other heteroatom selected from the group consisting of
nitrogen, oxygen and sulfur;
R and R10 are each independently alkyl, H, -C(0)Ar, -C(0)NH(CH 2)wNH2, -C(0)alkyl;
n is an integer from 0-4;
m is an integer from 0-2;
p is an integer from 0-4;
q is an integer from 0-10;
t is an integer from 1-10;
w is an integer from 1-10;
Ar is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl group optionally substituted with
at least one of halogen, OH, COOH, S0 3H, NH2, N0 2, CONHNH2, alkyl, or alkoxy;wherein at least one of Rl
R2, R3, R4 and Ar is optionally a radionuclide or optionally
substituted with a radionuclide; and with the proviso that said Compound of Formula (I)
is not 2-(4-(amino)phenyl)quinoline (BF-170); 2-(4-(methylamino)phenyl)quinoline
(BF-158); 2-(4-(dimethylamino)phenyl)quinoline (N-310); 2-(4-
(diethylamino)phenyl)quinoline (N-313); 2-(4-aminophenyl)-6-bromo-4-
carbazoylquinoline (N-311); potassium 2-(4-aminophenyl)-quinoline-4-carboxylate (N-
312); or 2-(4-(dimethylamino)phenyl)-7-methylquinoline (SA-820).
The present invention further provides a pharmaceutical composition
comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or
excipient.
The present invention further provides a method of making a compound of
Formula (I).
The present invention further provides a method of imaging using a compound
of Formula (I) or a pharmaceutical composition thereof.
The present invention further provides a method of detecting tau aggregates in
vitro and/or vivo using a compound of Formula (I) or a pharmaceutical composition
thereof.
Detailed Description of the Invention
The present invention provides quinoline compounds of Formula (I) as
described herein.
In a preferred embodiment of the invention, a compound of Formula (I), as
described above, is provided wherein Ar is selected from the group consisting of:
, and
with the proviso that when Ar is a phenyl group said Compound of Formula (I) is not 2-
(4-(amino)phenyl)quinoline (BF-170); 2-(4-(methylamino)phenyl)quinoline (BF-158);
2-(4-(dimethylamino)phenyl)quinoline (N-310); 2-(4-(diethylamino)phenyl)quinoline
(N-313); 2-(4-aminophenyl)-6-bromo-4-carbazoylquinoline (N-311); potassium 2-(4-aminophenyl)-quinoline-4-carboxylate (N-312); or 2-(4-(dimethylamino)phenyl)-7-
methylquinoline (SA-820).
The present invention provides a compound of Formula (I) having Formula (la):
wherein Ri, R2, R4, n, m and p are each as defined herein for a compound of Formula (I)
with the proviso that said Compound of Formula (la) is not 2-(4-
(amino)phenyl)quinoline (BF-170); 2-(4-(methylamino)phenyl)quinoline (BF-158); 2-
(4-(dimethylamino)phenyl)quinoline (N-310); 2-(4-(diethylamino)phenyl)quinoline (N-
313); 2-(4-aminophenyl)-6-bromo-4-carbazoylquinoline (N-311); potassium 2-(4-
aminophenyl)-quinoline-4-carboxylate (N-312); or 2-(4-(dimethylamino)phenyl)-7-
methylquinoline (SA-820).
The present invention provides a compound of Formula (I) having Formula (II):
wherein R2, n and m are each as defined herein for a compound of Formula (I) and
R6 is H,Me, or CH2CH2F.
The present invention provides a compound of Formula (I) having Formula (ΙΠ)wherein Ri, R2, n and m are each as defined herein for a compound of Formula (I).
The present invention provides a compound of Formula (I) having Formula (IV):
wherein Ri, R2, n and m are each as defined herein for a compound of Formula (I).
The present invention provides a compound of Formula (I) having Formula (V):
wherein Ri, R2, n and m are each as defined herein for a compound of Formula (I) and
R6 is H,Me, or CH2CH2F.
The present invention provides a compound of Formulae (VI) and (Via):wherein Ri, R2 , R5, R6 , n and m are each as defined herein for a compound of Formula
(I) .
The present invention provides a compound of Formulae (VII) and (Vila):
wherein Ri, R2 , R4 , R6 , Ar, n, m and p found in Formulae (VII) and (Vila) are each as
defined herein for a compound of Formula (I).The present invention provides a compound of Formulae (VIII) and (Villa):
wherein Ri, R2, R4, Ar, n, m and p found in Formulae (VIII) and (Villa) are each
defined herein for a compound of Formula (I).
The present invention provides a compound of Formulae (IX) and (EXa):
wherein Rl
R2, R4, Ar, n, m and p found in Formulae (EX) and (EXa) are each as defined
herein for a compound of Formula (I).-9-The present invention provides a compound of Formula (I) selected from the
group consisting of:
wherein X and Y are each independently OH, OR3, N(R3)
2, C0 2R, C0 2N(R3 ) 2 or
S0 2N(R ) 2 where R3 is as defined herein; and Het is a heterocyclic group.
The present invention provides a compound of Formula (I) selected from the
group consisting of:wherein "F" of each of the structures can be either cold fluorine (F) or radioisotopic
fluorine (e.g.
1 F) and R is as defined for a compound of Formula (I).
The present invention provides a compound of Formula (I) selected from the
group consisting of:wherein R is as defined for a compound of Formula (I).
According to the present invention, for a compound of the invention described
herein, a halogen is selected from F, CI, Br, and I ; preferably, F.
According to the present invention, for a compound of the invention described
herein, a radionuclide shall mean any radioisotope known in the art (hereinafter referred
to as a "radiolabeled compound"). Preferably the radionuclide is a radioisotope suitable
for imaging (e.g., PET, SPECT). In one embodiment, the radionuclide is a radioisotope
suitable for PET imaging. Even more preferably, the radionuclide is C,
1 N,
150 ,
6 Ga,
6 Cu,
1 F,
6Br,
124I, or 125I ; even more preferably, the radionuclide is 1 F .
In one embodiment, the radionuclide is a radioisotope suitable for SPECT
imaging. Even more preferably, the radionuclide is mTc,
1 ln,
6 Ga,
1T1,
1 I, or
1 Xe; even more preferably, the radionuclide is mTc or 1 I .
Pharmaceutical or Radiopharmaceutical Composition
The present invention provides a pharmaceutical or radiopharmaceutical
composition comprising a compound of the invention as described herein together with
a pharmaceutically acceptable carrier, excipient, or biocompatible carrier. According
to the invention when a compound of the invention is radiolabeled with a radionuclide,
the pharmaceutical composition is a radiopharmaceutical composition.
The present invention further provides a pharmaceutical or radiopharmaceutical
composition comprising a compound of the invention as described herein together with
a pharmaceutically acceptable carrier, excipient, or biocompatible carrier suitable for
mammalian administration.
As would be understood by one of skill in the art, the pharmaceutically
acceptable carrier or excipient can be any pharmaceutically acceptable carrier or
excipient known in the art.
The "biocompatible carrier" can be any fluid, especially a liquid, in which a
compound of the invention can be suspended or dissolved, such that the pharmaceutical
composition is physiologically tolerable, e.g., can be administered to the mammalian
body without toxicity or undue discomfort. The biocompatible carrier is suitably an
injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueoussolution such as saline (which may advantageously be balanced so that the final product
for injection is either isotonic or not hypotonic); an aqueous solution of one or more
tonicity-adjusting substances (e.g., salts of plasma cations with biocompatible
counterions), sugars (e.g., glucose or sucrose), sugar alcohols (e.g., sorbitol or
mannitol), glycols (e.g., glycerol), or other non-ionic polyol materials (e.g.,
polyethyleneglycols, propylene glycols and the like). The biocompatible carrier may
also comprise biocompatible organic solvents such as ethanol. Such organic solvents
are useful to solubilise more lipophilic compounds or formulations. Preferably the
biocompatible carrier is pyrogen-free water for injection, isotonic saline or an aqueous
ethanol solution. The pH of the biocompatible carrier for intravenous injection is
suitably in the range 4.0 to 10.5.
The pharmaceutical or radiopharmaceutical composition may be administered
parenterally, i.e., by injection, and is most preferably an aqueous solution. Such a
composition may optionally contain further ingredients such as buffers;
pharmaceutically acceptable solubilisers (e.g., cyclodextrins or surfactants such as
Pluronic, Tween or phospholipids); pharmaceutically acceptable stabilisers or
antioxidants (such as ascorbic acid, gentisic acid or /rara-aminobenzoic acid). Where a
compound of the invention is provided as a radiopharmaceutical composition, the
method for preparation of said compound may further comprise the steps required to
obtain a radiopharmaceutical composition, e.g., removal of organic solvent, addition of
a biocompatible buffer and any optional further ingredients. For parenteral
administration, steps to ensure that the radiopharmaceutical composition is sterile and
apyrogenic also need to be taken. Such steps are well-known to those of skill in the art.
Preparation of a Compound of the Invention
A compound of the invention may be prepared by any means known in the art
including, but not limited to, nucleophilic aromatic substitution, nucleophilic aliphatic
substitution, and click chemistry.
In one embodiment of the invention, a compound of the invention may be
halogenated or radiolabeled with a radionuclide by nucleophilic aromatic substitution ornucleophilic aliphatic substitution of an appropriate leaving group with the desired
halogen or radionuclide. Examples of suitable leaving groups for nucleophilic aromatic
substitution include, but are not limited to, CI, Br, F, N0 2 and +N(R)
4. Examples of
suitable leaving groups for nucleophilic aliphatic substitution include, but are not
limited to, I, Br, CI, and OTs (tosylate).
In one embodiment, a compound of the invention may be prepared by means of
the Suzuki reaction viz:
ava a e rom ava a e rom
ALD RIC H ALD RICH
Isoquinoline compounds of the invention may be prepared in a similar fashion
starting with bromo-isoquinoline.
In one embodiment, a compound of the invention may be prepared according to
the following Scheme I :Substituted bulky aromatic groups could also be attached to the aniline.
In one embodiment, a compound of the invention may be prepared via reductive
amination with aniline and substituted aldehydes:
in several ways: including nucleophilic aromatic substitution on activated rings such as
pyridine and quinoline and nucleophilic aliphatic substitution viz:By way of example, the radioisotope [ F]-fluoride ion ( F ) is normally obtained as an
aqueous solution from the nuclear reaction 1 0(p,n) 1 F and is made reactive by the
addition of a cationic counterion and the subsequent removal of water. Suitable cationic
counterions should possess sufficient solubility within the anhydrous reaction solvent to
maintain the solubility of 18F . Therefore, counterions that have been used include
large but soft metal ions such as rubidium or caesium, potassium complexed with a
cryptand such as Kryptofix™, or tetraalkylammonium salts. A preferred counterion is
potassium complexed with a cryptand such as Kryptofix™ because of its good
solubility in anhydrous solvents and enhanced 18
F-
reactivity.
18
F can also be
introduced by nucleophilic displacement of a suitable leaving group such as a halogen
or tosylate group. A more detailed discussion of well-known 18
F labelling techniques
can be found in Chapter 6 of the "Handbook of Radiopharmaceuticals" (2003; John
Wiley and Sons: M.J. Welch and C.S. Redvanly, Eds.). Similar methods may be used
to radiolabel a compound of the invention with other radioisotopes including the PET
and SPECT radioisotopes described herein.
Automated Synthesis
In one embodiment, the method to prepare a radiolabeled compound of the
invention, each as described herein, is automated. For example, [
18
F]-labeledcompounds of the invention may be conveniently prepared in an automated fashion by
means of an automated radiosynthesis apparatus. There are several commercially-
available examples of such platform apparatus, including TRACERlab™ (e.g.,
TRACERlab™ MX) and FASTlab™ (both from GE Healthcare Ltd.). Such apparatus
commonly comprises a "cassette", often disposable, in which the radiochemistry is
performed, which is fitted to the apparatus in order to perform a radiosynthesis. The
cassette normally includes fluid pathways, a reaction vessel, and ports for receiving
reagent vials as well as any solid-phase extraction cartridges used in post-radiosynthetic
clean up steps. Optionally, in a further embodiment of the invention, the automated
radiosynthesis apparatus can be linked to a high performance liquid chromatograph
(HPLC). The present invention therefore provides a cassette for the automated
synthesis of a compound of the invention.
Imaging Method
The radiolabeled compound of the invention, as described herein, may bind to
NFTs or tau aggregates and aid in identifying the amount of NFTs/tau aggregates
present which in turn may correlate with the stage of AD.
The present invention thus provides a method of imaging comprising the step of
administering a radiolabeled compound of the invention, as described herein, to a
subject and detecting said radiolabeled compound of the invention in said subject. The
present invention further provides a method of detecting tau aggregates in vitro or in
vivo using a radiolabeled compound of the invention, as described herein. Hence the
present invention provides better tools for early detection and diagnosis of Alzheimers
disease. The present invention also provides better tools for monitoring the progression
of Alzheimers disease and the effect of treatment.
As would be understood by one of skill in the art the type of imaging (e.g., PET,
SPECT) will be determined by the nature of the radioisotope. For example, if the
18
radiolabeled compound of the invention contains F it will be suitable for PET
imaging.
Thus the invention provides amethod of detecting tau aggregates in vitro or in vivo
comprising the steps of:administering to a subject a radiolabeled compound of the invention as
defined herein;
allowing said a radiolabeled compound of the invention to bind to NFTs
in said subject;
detecting signals emitted by said radioisotope in said bound
radiolabeled compound of the invention;
generating an image representative of the location and/or amount of said
signals; and,
determining the distribution and extent of said tau aggregates in said
subject.
The step of "administering" a radiolabeled compound of the invention is preferably
carried out parenterally, and most preferably intravenously. The intravenous route
represents the most efficient way to deliver the compound throughout the body of the
subject. Intravenous administration neither represents a substantial physical intervention
nor a substantial health risk to the subject. The radiolabeled compound of the invention is
preferably administered as the radiopharmaceutical composition of the invention, as
defined herein. The administration step is not required for a complete definition of the
imaging method of the invention. As such, the imaging method of the invention can also
be understood as comprising the above-defined steps (ii)-(v) carried out on a subject to
whom a radiolabeled compound of the invention has been pre-administered.
Following the administering step and preceding the detecting step, the radiolabeled
compound of the invention is allowed to bind to the tau aggregates. For example, when the
subject is an intact mammal, the radiolabeled compound of the invention will dynamically
move through the mammal ' s body, coming into contact with various tissues therein. Once
the radiolabeled compound of the invention comes into contact with the tau aggregates it
will bind to the tau aggregates.
The "detecting" step of the method of the invention involves detection of signals
emitted by the radioisotope comprised in the radiolabeled compound of the invention by
means of a detector sensitive to said signals, e.g., a PET camera. This detection step can
also be understood as the acquisition of signal data.The "generating" step of the method of the invention is carried out by a computer
which applies a reconstruction algorithm to the acquired signal data to yield a dataset. This
dataset is then manipulated to generate images showing the location and/or amount of
signals emitted by the radioisotope. The signals emitted directly correlate with the amount
of enzyme or neoplastic tissue such that the "determining" step can be made by evaluating
the generated image.
The "subject" of the invention can be any human or animal subject. Preferably the
subject of the invention is amammal. Most preferably, said subject is an intactmammalian
body in vivo. In an especially preferred embodiment, the subject of the invention is a
human.
The "disease state associated with the tau aggregates" can beMCI (mild cognitive
impairment), dementia or Alzheimers disease.
All patents, journal articles, publications and other documents discussed and/or
cited above are hereby incorporated by reference.What is claimed is:
1. A compound of Formula I :
wherein:
Ri is independently H, halogen, OH, COOH, S0 3H, NH2, N0 2, CONHNH2, alkyl, or
alkoxy;
R2 is independently H, halogen, OH, COOH, S0 3H, NH2, N0 2, CONHNH2, alkyl, or
alkoxy;
R4 is independently H or NR5R 6 where R and R are each independently H, alkyl,
haloalkyl, -(CH )
qOR7, -(CH )
qO(CH ) OR7, -(CH )
qNR7R , -(CH ) aryl, -
(CH2)
qheteroaryl, -(CH2)
qheterocyclyl, where R and R may be further optionally
substituted with at least one group selected from the group consisting of -OH, -OR 3,
N(R3)
2, C(0)OR 3, C(0)N(R 3)
2, S0 2N(R3)
2where R3 is independently H, alkyl, aryl,
heteroaryl, heterocyclyl, cycloalkyl, wherein R3 is further optionally substituted; or R
and R taken together taken together with the nitrogen to which they are attached form a
cyclic or aromatic moiety which optionally contains at least one other heteroatom
selected from the group consisting of nitrogen, oxygen and sulfur and which is
optionally substituted with at least one of halogen, OH, COOH, S0 H, NH2, N0 2,
CONHNHz, alkyl, or alkoxy;
R 7 and R are each independently H, alkyl, -(CH2)
t
NR R io or R 7 and R taken together
with the nitrogen to which they are attached form a cyclic or aromatic moiety which
optionally contains at least one other heteroatom selected from the group consisting of
nitrogen, oxygen and sulfur;R and R10 are each independently alkyl, H, -C(0)Ar, -C(0)NH(CH 2)wNH2, -C(0)alkyl;
n is an integer from 0-4;
m is an integer from 0-2;
p is an integer from 0-4;
q is an integer from 0-10;
t is an integer from 1-10;
w is an integer from 1-10;
Ar is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl group optionally substituted with
at least one of halogen, OH, COOH, S0 3H, NH2, N0 2, CONHNH2, alkyl, or alkoxy;
wherein at least one of Ri, R2, R3, R4 and Ar is optionally a radionuclide or optionally
substituted with a radionuclide; and with the proviso that said Compound of Formula (I)
is not 2-(4-(amino)phenyl)quinoline (BF-170); 2-(4-(methylamino)phenyl)quinoline
(BF-158); 2-(4-(dimethylamino)phenyl)quinoline (N-310); 2-(4-
(diethylamino)phenyl)quinoline (N-3 13) ; 2-(4-aminophenyl)-6-bromo-4-
carbazoylquinoline (N-3 11); potassium 2-(4-aminophenyl)-quinoline-4-carboxylate (N-
312); or 2-(4-(dimethylamino)phenyl)-7-methylquinoline (SA-820).
2. A compound according to claim 1wherein Ar is selected from the group
consisting of:
with the proviso that when Ar is a phenyl group said Compound of Formula (I) is not 2-
(4-(amino)phenyl)quinoline (BF-170); 2-(4-(methylamino)phenyl)quinoline (BF-158);
2-(4-(dimethylamino)phenyl)quinoline (N-310); 2-(4-(diethylamino)phenyl)quinoline
(N-313); 2-(4-aminophenyl)-6-bromo-4-carbazoylquinoline (N-311); potassium 2-(4-aminophenyl)-quinoline-4-carboxylate (N-312); or 2-(4-(dimethylamino)phenyl)-7-
methylquinoline (SA-820).
3. A compound according to Claim 1 having Formula (la):
wherein Ri, R2, R4, n, m and p are each as defined herein for a compound of Formula (I)
with the proviso that said Compound of Formula (la) is not 2-(4-
(amino)phenyl)quinoline (BF-170); 2-(4-(methylamino)phenyl)quinoline (BF-158); 2-
(4-(dimethylamino)phenyl)quinoline (N-310); 2-(4-(diethylamino)phenyl)quinoline (N-
313); 2-(4-aminophenyl)-6-bromo-4-carbazoylquinoline (N-311); potassium 2-(4-
aminophenyl)-quinoline-4-carboxylate (N-312); or 2-(4-(dimethylamino)phenyl)-7-
methylquinoline (SA-820).
4. A compound according to Claim 1 having Formula (Π) :
wherein Rl
R2, n and m are each as defined herein for a compound of Formula (I) and
R6 is H,Me, or CH2CH2F.5. A compound according to Claim 1 having Formula (ΠΙ ) :
wherein Ri, R2, n and m are each as defined herein for a compound of Formula (I).
6. A compound according to Claim 1 having Formula (IV):
wherein Ri, R2, n and m are each as defined herein for a compound of Formula (I).
7. A compound according to Claim 1 having Formula (V):
wherein Ri, R2, n and m are each as defined herein for a compound of Formula (I) andR6 is H,Me, or CH2CH2F.
8. A compound of Formulae (VI) and (Via):
wherein Rl
R2, R5, R6, n and m are each as defined herein for a compound of
(I) .
9. A compound of Formulae (VII) and (Vila):wherein Ri, R2 , R4 , R6 , Ar, n, m and p found in Formulae (VII) and (Vila) are each as
defined herein for a compound of Formula (I).
10. A compound of Formulae (VIII) and (Villa):
wherein Ri, R2 , R4 , Ar, n, m and p found in Formulae (VIII) and (Villa) are each as
defined herein for a compound of Formula (I).
11. A compound of Formulae (FX) and (Ka):wherein Ri, R2, R4, Ar, n, m and p found in Formulae (FX) and (FXa) are each as defined
herein for a compound of Formula (I).
wherein Ri, R2, R5, R6, n and m are each as defined herein for a compound of Formula
C D
12. A compound according to Claim 1 selected from the group consisting of:-27-wherein X and Y are each independently OH, OR3, N(R3)
2, C0 2R, C0 2N(R3)
2 or
S0 2N(R3)
2 where R3 is as defined herein; and Het is a heterocyclic group.
14. A compound according to Claim 1 selected from the group consisting of:wherein "F" of each of the structures can be either cold fluorine (F) or radioisotopic
fluorine (e.g.
1 F) and R is as defined for a compound of Formula (I).
15. A compound according to Claim 1 selected from the group consisting of:
wherein R is as defined for a compound of Formula (I).
16. A pharmaceutical composition comprising a compound according to any one of
claims 1-15 and a pharmaceutically acceptable carrier or excipient.
17. A method of making a compound according to any one of claims 1-15.
18. A method of imaging using a compound according to any one of claims 1-15 or a
pharmaceutical composition thereof.
19. A method of detecting tau aggregates in vitro and/or in vivo using a compound
according to any one of claims 1-15 or a pharmaceutical composition thereof.