Synthesis of [{sup 18}F]Ro41-0960, a potent COMT inhibitor, for use in vivo mapping with PET

Journal Article · Mon May 01 00:00:00 EDT 1995 · Journal of Nuclear Medicine

OSTI ID:441626

Ding, Y S; Sugano, Y; Gatley, S J ^[1]

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1. Brookhaven National Laboratory, Upton, NY (United States); and others

Catechol-O-methyltransferase (COMPT; EC 2.1.1.6) is one of the two major enzymes which metabolize the catecholamine neurotransmitters. It is distributed throughout the body and brain and is elevated in breast cancer tissue when it plays a role in estrogen metabolism. It is also an important molecular target in the development of drugs to treat Parkinson`s disease (PD). Because COMT regulates the concentration of important neurotransmitter amines such as dopamine, there is speculation that abnormalities in its activity may be associated with neurological, and psychiatric disorders. Ro41-9060(3,4-dihydroxy-5-nitro-2{prime}-fluorobenzophenone) is a potent, fluorine containing COMT inhibitor which has been reported to cross the blood brain barrier. It is structurally similar to Ro40-7592 which is currently undergoing clinical trials in PD. We report the synthesis of [{sup 18}F]Ro41-0960, for investigation for mapping COMT and for studies of COMT drugs. [{sup 18}F]Ro41-0960 was synthesized by the nucleophilic aromatic substitution reaction with NCA [{sup 18}F] fluoride on a protected precursor (prepared via a five-step synthesis) followed by hydrolysis with HBr (synthesis time of 100 min; radiochemical yield of 5-7% (EOB)). Though Ro41-0960 has been reported to cross the blood brain barrier, PET studies in baboon demonstrated that an almost complete absence of the drug from the brain both at tracer doses and with the addition of unlabeled drug (1.5 mg/kg) at all times through a 90 min experimental interval. The plasma to brain ratios of F-18 average about 40:1. However, high uptake was observed in the kidneys and in other organs which are known to have high COMT. Studies in mice showed that at 30 min after injection of tracer, F-18 in kidneys was largely as [{sup 18}F]Ro-41-0960 and that it could be displaced with unlabeled Ro41-0960. These studies provide the first example of a positron emitter labeled COMT radiotracer.

• OSTI ID: 441626
• Report Number(s): CONF-950603--
• Journal Information: Journal of Nuclear Medicine, Journal Name: Journal of Nuclear Medicine Journal Issue: Suppl.5 Vol. 36; ISSN 0161-5505; ISSN JNMEAQ
• Country of Publication: United States
• Language: English

Related Subjects

40 CHEMISTRY
55 BIOLOGY AND MEDICINE
BASIC STUDIES
BENZOPHENONE
CATECHOLAMINES
CHEMICAL PREPARATION
DIAGNOSTIC TECHNIQUES
DOPAMINE
ENZYME ACTIVITY
ENZYME INHIBITORS
FLUORINE 18
HYDROLYSIS
KIDNEYS
LABELLED COMPOUNDS
METABOLISM
METHYL TRANSFERASES
MICE
NERVOUS SYSTEM DISEASES
ORGANIC FLUORINE COMPOUNDS
POSITRON COMPUTED TOMOGRAPHY
PYROCATECHOL
THERAPY
TRACER TECHNIQUES
UPTAKE