Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1993-03-23
1995-05-09
Lovering, Richard D.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
546132, A61K 4902, C07D45102
Patent
active
054137799
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention is directed to a binding ligand for cocaine and other receptors in the brain. Specifically, a novel family of compounds, represented by 3.beta.-[4-iodophenyl]-tropan-2.beta.-carboxylic acid methyl ester (RTI-55) tartrate shows high binding specificity and activity, and, in a radiolabeled form, can be used to bind these receptors, for biochemical or imaging techniques.
BACKGROUND ART
Continuing attempts to understand, diagnose, treat and prevent neural disorders rely, in part, on localization or imaging techniques, allowing researchers to determine the location, number and size of specific neurological phenomena. Among those sites undergoing specific testing are cocaine receptors associated with dopamine and serotonin transporter sites.
In order to be useful as a binding ligand for these types of imaging techniques, the compound must have a high affinity for the receptors in question. One such example is the tritiated compound [.sup.3 H]WIN 35,428, discussed in conjunction with the protocol for determining the relative affinity in binding ligands set forth in the presentation of Carroll et al, 19th Annual FASEB Meeting, Washington, D.C. (1990) incorporated herein-by-reference. Compounds exhibiting high affinity have previously been demonstrated to be useful as binding ligands, in in vitro and in vivo processes. Madras et al, Molecular Pharmacology, 36, 518-524 (1989) and Scheffel et al, Synapse, 4, 390-394 (1989) both incorporated by reference.
In processes of this type, a radioactively labeled, or similarly labeled compound is administered or injected, depending on in vivo or in vitro processing, and allowed to bind to the transporter sites in question. Thereafter, those sites actually bound to can be determined, by radiographic imaging techniques and the like. In one example, diagnosis of Parkinson's disease may be accomplished by administering a binding ligand having a high affinity for dopamine transporters, and subsequently subjecting the brain to SPECT scanning. The relative frequency of bound sites and imaging obtained allows an assessment of the presence or absence of Parkinson's disease.
Many radioactively labeled ligands, such as the tritiated compound discussed above, or other tritiated or carbon-14 labeled compounds lack sufficient specific activity or affinity are subject to specimen quenching and absorption. Additionally, ideal radiolabeled binding ligands should be useful in powerful scanning and imaging techniques, such as SPECT (Single Photon Emission Computed Tomography) scanning and the like. Thus, improved binding ligands exhibiting these advantages continue to be an object of those of skill in the art.
DISCLOSURE OF THE INVENTION
The family of compounds having the following structure: ##STR1## wherein R.sub.1 =(CH.sub.2).sub.n CH.sub.3, n=0-6; CH.sub.2 CR.sub.3 .dbd.CR.sub.4 R.sub.5 (R.sub.3, R.sub.4, R.sub.5 are all, independently, C.sub.1 -C.sub.6 alkyl); (CH.sub.2).sub.y C.sub.6 H.sub.5, y=1-6;
R.sub.2 =CH.sub.3, C.sub.2 H.sub.5, CH.sub.3 (CH.sub.2).sub.3, (CH.sub.3).sub.2 CH, C.sub.6 H.sub.5, C.sub.6 H.sub.5 CH.sub.2, C.sub.6 H.sub.5 (CH.sub.2).sub.z, z=1-6;
X=pharmacologically acceptable anion. (RTI-55) tartrate is an example have been demonstrated to have a high affinity for binding to cocaine receptors, among them the dopamine transporters in the brain. Additionally, RTI-55 has been demonstrated to have an extremely high affinity for another cocaine receptor, serotonin transporters. As this class of compounds bears an iodine atom, this atom can be substituted with a radioactive isotope, such as I-125, I-123 or I-131. Iodinated compounds of this type have advantages over prior art tritiated or carbon-14 labeled compounds. Notably, the high specific activity, reduced specimen quenching and absorption, and susceptibility for use in SPECT scanning and the like, offers advantages not found in prior art compounds. Additionally, these compounds are much easier to make.
3.beta.-[4-iodophenyl]-tropan-2.beta.-carboxylic acid methyl ester (RTI-55) is an
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Chemical Abstract 112(1):539p.
Molecular Pharmacology, vol. 36, No. 4, 1989, (USA); Madras et al.: "Cocaine Receptors Labeled by [3H]2..beta..-Carbomethoxy-3..beta..-(4-Fluorophenyl) Tropane", pp. 518-524.
Abraham Philip
Boja John W.
Carroll Frank I.
Kuhar Michael J.
Lewin Anita H.
Covert John M.
Lovering Richard D.
Research Triangle Institute
The United States of America represented by the Secretary of Hea
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