Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2001-01-19
2003-01-21
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C514S327000, C546S242000, C546S221000, C546S222000, C424S009440
Reexamination Certificate
active
06509003
ABSTRACT:
TECHNICAL FIELD
The present invention relates to N-alkylpiperidine derivatives and reagents including the derivatives used for the determination of cerebral regional acetylcholinesterase (AchE) activity.
BACKGROUND ART
Cerebral cholinergic nerve system plays an important role in memory function. Degeneration of this nerve system is thought to be implicated in memory impairment seen in dementing disorders such as Alzheimeer's disease. The AchE activity has been found to be reduced in accordance with the decreased cholinergic function in the brain. The determination of cerebral regional AchE activity may, therefore, contribute greatly to clinical diagnosis, therapeutic evaluation and pathological elucidation of dementing and/or age-related neurological disorders.
Conventionally, AchE activity in the brain has been determined enzymatically or histochemically using homogenate or sections of postmortem brain tissue. Lipophilic acetylcholine analogs labeled with radionuclide have also been used to determine AchE activity in the brain by using autoradiagraphy or emission tomography (Japanese Patent Application laid-open No. 327497/1994). The emission tomographic method allows non-invasive determination of AchE activity in the living brain in both human and animal subjects. This method has been found to be of merit for clinical diagnosis or development of therapeutic drugs for degenerative disorders of cholinergic nerve system including Alzheimer's disease (Namba et. el., Brain Res., 667:278-282, 1994, Irie et. al., J. Nucl. Med., 37:649-655, 1996).
The radiolabeled compounds used in the method described in above publications must have following characteristics:
(1) Highly lipophilic to pass through the blood-brain barrier easily;
(2) Being specifically hydrolyzed by AchE in the brain;
(3) Being hydrolyzed to less lipophilic alcohol that is trapped in the brain; and
(4) Negligible cerebral incorporation of the hydrolyzed alcohol formed outside the brain.
The above application have shown the following radiolabeled compounds satisfying the above requirements; N-methylpiperidinyl-3-acetate, N-methylpiperidinyl-3-propionate, N-methylpiperidinyl-4-acetate and N-methylpiperidinyl-4-propionate, each of which has N-methyl group labeled with
14
C. By using these compounds, autoradiographic determination of cerebral AchE activity ahs been achieved in rats. Furthermore, positron emission tomography (PET) using the
11
C labeled compound has been done for non-invasive determination of cerebral AchE activity in living subjects (Iyo el. Al., Lancet, 349:1805-1809, 1997)
The conventional lipophilic acetylcholine analogs including the compounds described above, however, allow only
11
C-labeling to give practically available radiolabeled compounds used for non-invasive determination of cerebral AchE activity. Therefore, PET using positron camera is the only selection allowed to be used for clinical application to human subjects. Because of the short half-life of
11
C (about 20 min), PET scanning is restricted to performing in a facility with a cyclotron for radioisotope production. Meanwhile, single photon emission computed tomography (SPECT) using gamma camera is widely used for clinical practice, so the development of a radiolabeled compound applicable to SPECT has been demanded.
DISCLOSURE OF THE INVENTION
The present inventors have performed earnest studies on compounds labeled with an appropriate gamma-ray emitting radionuclide with a view to developing an AchE activity imaging SPECT agent fulfilling the required characteristics, and have found novel N-alkylpiperidine derivatives labeled with radioactive iodine.
The present invention provides N-alkylpiperidine derivatives and their salts represented by the following general formula (1) or (2);
wherein R
1
represents a lower alkyl group which may be substituted by a fluorine atom; R
2
represents a lower alkyl group; and R
3
represents an alkenyl group which is substituted at its 1-position by a hydroxy group, a lower alkoxy group, a lower alkoxyalkyloxy group, a lower alkoxyalkyloxyalkyloxy group, or a lower alkanoyloxy group and is substituted at the end by radioactive iodine, or an alkenyloxymethyl group which is substituted at an the end by radioactive iodine.
The present invention also provides a reagent for the determination of AchE activity including the N-alkylpiperidine derivatives and their salts.
The present invention also provides the method for the determination of cerebral regional AchE activity using the N-alkylpiperidine derivatives and their salts.
The present invention also provides precursors of the radioactive N-alkylpiperidine derivatives and their salts, represented by the following general formula (1P) or (2P);
wherein R
1
represents an lower alkyl group which may be substituted by a fluorine atom; R
2
represents a lower alkyl group; and R
3P
represents an alkenyl group which is substituted at its 1-position by a hydroxy group, a lower alkoxy group, a lower alkoxyalkyloxy group, a lower alkoxyalkyloxyalkyloxy group, or a lower alkanoyloxy group and is substituted at the end by a non-radioactive halogen atom, a trialkyltin group, or a trialkylsilyl group, or an alkenyloxymethyl group which is substituted at the end by non-radioactive halogen atom, a trialkyltin group, or a trialkylsilyl group.
REFERENCES:
patent: 63-39860 (1988-02-01), None
Toshiaki IRIE, et al., J. Nucl. Med., vol. 37, No. 4, pp. 649-655, “Brain Acetylocholinesterase Activity: Validation of a Pet Tracer in a Rat Model of Alzheimer's Disease”, Apr. 1996.
Journal of Medicinal Chemistry, vol. 16(2), 156-159(1973).
Fukushi Kiyoshi
Ikota Nobuo
Irie Toshiaki
Iyo Masaomi
Nagatsuka Shinichiro
Daiichi Pure Chemicals Co. Ltd.
Huang Evelyn Mei
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