Tomas De Paulis

Preparation of 11C-labelled raclopride, a new potent dopamine receptor antagonist: Preliminary PET studies of cerebral dopamine receptors in the monkey

A new dopamine receptor antagonist, Raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy- 6-methoxybenzamide, FLA 870) (1), has been labelled using [11C]ethyl iodide for alkylation of the nitrogen of the pyrrolidine ring in the corresponding secondary amine (5). The synthesis of 5 and an efficient method for the preparation of [11C]ethyl iodide are described. The 11C-labelled FLA 870 (1) was purified by HPLC and then used in positron emission tomography to visualize the dopamine receptor-rich areas of the monkey brain. The images obtained show selective accumulation of FLA 870 in striatum and a 10-fold separation between the binding to caudate vs cerebellum.

Chapter 3. Antipsychotic Agents and Dopamine Agonists

Publisher Summary A large number of new compounds are being developed as anti-psychotics, many inspired by the atypical drugs clozapine and sulpiride. The emergence of selective presynaptic dopamine (DA) agonists instead of conventional DA blockers has increased strongly. New insight has been gained in the function and biochemistry of DA receptors that circumstantially are involved in the pathophysiology of schizophrenia and other disease. The unique profile of clozapine is suggested to depend on its anti-cholinergic effect or on its specific DA-blockade in the mesolimbic system. Studies of drug-induced elevation of acetylcholine have indicated that only the D-2 receptor is involved in the regulation of striatal cholinergic transmission, and subsequently involved in the extrapyramidal function. The ability of neuroleptics to antagonize hypothermia in rats induced by sub-stereotypic doses of apomorphine is found to correlate to antipsychotic activity in man. The continued interest in the DA receptor agonists in the central nervous system (CNS) seems to focus on two aspects. It is required to find selective agents that stimulate only the presynaptic DA receptor, thereby giving the possibility of treating mental disorders, in which neuronal DA hyperactivity is the pathophysiological condition as an alternative to neuroleptic therapy. The other is to find agents that stimulate only the postsynaptic DA receptor, thereby overcoming DA deficiency diseases, such as parkinsonism. Additional pharmacological and chemical objectives are to find agonists that are able to induce specific behavioral effects for use in the animal models and to gain topographical knowledge of the DA receptor through these agonists in view of the mounting evidence that the structural requirements for agonist receptor affinity may be different from those of the DA antagonist. Recent commentaries on the nomenclature of central and peripheral DA receptors have appeared.