Dopamine transporter imaging ligand

Details Dopamine transporter imaging ligand Dopamine transporter imaging ligand

1997-10-07

2002-03-19

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C546S132000

Reexamination Certificate

active

06358492

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to novel dopamine transporter imaging ligands that exhibit high selectivity for dopamine transport combined with a rapid apparent equilibrium of striatal-to-cerebellar ratios.
2. Discussion of the Related Art
Since the initial preparation by Clarke and co-workers over twenty-three years ago, (Clarke et al, J. Med. Chem., 16, 1260-1267 1973), the 3&bgr;-(substituted phenyl)tropane-2&bgr;-carboxylic acid methyl ester class of compounds has been widely employed in structure-activity relationship (SAR) studies at the cocaine binding site on the dopamine transporter (DAT).
The 3&bgr; (substituted phenyl)tropane-2&bgr;-carboxylic acid esters are effective in vivo binding ligands for dopamine transporters (DATS) (Scheffel and Kuhar, Synapse 4:390-392, 1989; Boja et al., Dopamine Receptors & Transporters, 611-694, Marcel Dekker, Inc., 1994). For example, RTI-55, a member of this class, has been used in many studies in animals and humans as a Positron Emission Tomography (PET) or SPECT (single photon emission computed tomography) ligand (Boja et al., Ann. N.Y. Acad. of Sci. 654:282-291, 1992, and Boja et al., 1994). Highly desirable properties of a DAT ligand include rapid penetration into the brain, achievement of rapid apparent equilibrium, and high signal to noise ratios. Various 3&bgr;-phenyltropane analogs and other compounds possess these properties to varying degrees.
SUMMARY OF THE INVENTION
The 3&agr; isomer of RTI-55, RTI-352, is an effective in vivo binding ligand that reflects greater selectivity for the dopamine transporter than is observed with RTI-55. In addition, there is also a more rapid achievement of apparent equilibrium in the striatal-to-cerebellar ratio (compared to RTI-55) as the ratio peaks at about 30 min and is maintained for about 20 min thereafter. Such apparent equilibrium is useful in developing an approach to measuring the number of dopamine transporters present in tissues. Moreover, these results indicate that the utilization of 3&agr; isomers of a variety of 3&bgr;-(substituted phenyl)tropanes will result in greater selectivity for dopamine transporters and a more rapid achievement of apparent equilibrium.


REFERENCES:
patent: 5413779 (1995-05-01), Kuhar et al.
patent: 5439666 (1995-08-01), Neumeyer et al.
patent: WO 94/04146 (1994-03-01), None
Christopher R. Holmquistet al.,3&agr;-(4′-Substituted phenyl)Tropane-2&bgr;-carboxylic Acid Methyl Esters: Novel Ligands with High Affinity and Selectivity at the Dopamine Transporter, J. Med. Chem., 1996, vol. 39, pp. 4139-4141, XP002914107.
Kathryn I. Keverline et al.,Synthesis of the 2&bgr;,3&agr;-and 2&bgr;,3&bgr;-Isomers of 3-(p-lSubstitue Phenyl)Tropane-2-Carboxylic Acid Methyl Esters, Tetrahedron Letters, vol. 36, No. 18, pp. 3099-3102, 1995, XP004028199.
Kjell Nagren et al.,Comparison of -[11C] Methyl Triflate and [11C]Methyl Iodide in the Synthesis of PET Radioligands such as [11C]&bgr;-CIT and [11C]&bgr;-CFT,Nucl. Med. Biol., vol. 22, No. 8, pp. 965-970 1995, XP004051699.

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