J Neurol (1992) 239 [Suppl 1] :$17-$21 Journal of Neurology © Springer-Verlag1992 Retinal dopaminergic receptor affinity and ocular pharmacokinetic profile of piribedil P. Lapalus 1, P. Denis 2, M. Drici 1, D. Fredj-Reygrobellet 1, and P. P. Elena 3 1 Department of Experimental and Clinical Pharmacology, Facult6 de Mddecine, Avenue de Vallombrose, F-06034 Nice Cedex, France 2Clinical Ophthalmology, H6pital Saint Antoine, Paris, France 3Iris Pharma, La Gaude, France Summary. Binding studies on retinal dopamine recep- tors have revealed the existence of both D1 and D2 re- ceptors. Human retina micro-autoradiographs confirm the distribution of dopaminergic receptors in the plexi- form layers. Piribedil, a dopaminergic agonist, is able to bind to D2 receptors, while its metabolite ($584) pre- ferentially displaces Dl-specific radioligands. These re- suits demonstrate that piribedil has a dopamine-like phar- macological profile including direct interaction with re- ceptors. When instilled into the rabbit eye, piribedil penetrates rapidly and accumulates in the pigmented epithelia - the iris ciliary body and chorioretina - before being rapidly cleared. Macro-autoradiographs confirm this distribution and show the levels to be compatible with the affinity of piribedil for retinal dopaminergic re- ceptors. Key words: Human - Rabbit - Eye - Piribedil - Binding the radioligand binding activity of piribedil and its active metabolite ($584) with the dopaminergic binding sites in post-mortem human eyes, using micro-autoradiographs of retina sections. Moreover, as topical application is the most common route of administration for ophthalmic drugs, we have studied the ocular pharmacokinetic pro- file of piribedil, after instillation of one drop into the rabbit eye. Ocular and extra-ocular distribution of the radiolabelled compound, in eye sections was assessed using macro-autoradiographs. Materials and methods Materials and methods are briefly reported in the figure legends. Human retina micro-autoradiographs were performed after dopa- minergic receptor ligand displacement studies using piribedil and its metabolite ($584). Ocular distribution of piribedil after a single instillation into the rabbit eye was assessed by pharmacokinetic and autoradiographic methods in the pigmented rabbit. Introduction Piribedil is a dopaminergic agonist currently used in com- bination with levodopa, or alone, for the treatment of Parkinson's disease [4, 8]. It is considered to be a potent post-synaptic D2 receptor agonist [6]. Its ability to pene- trate the brain and more particularly cell membranes has allowed this drug to be tested in the ocular field, where dopamine has been shown to play an important role as a neurotransmitter in the retina of lower and higher verte- brates [1, 13]. Preliminary binding studies [5, 10] and clinical investigations of piribedil in contrast vision ab- normalities [3, 12] have already confirmed the potential of this drug to interact positively with impaired visual function linked to dopamine deficiency. Pharmacokinetic data on piribedil are now available [2, 18] and clearly indicate a high level of metabolism of this drug in man, with one predominant metabolite, hy- droxylated on the pyrimidyl ring ($3473). Four metabo- lites have been identified; one ($584) may play a role in the drug activity. Thus we felt it was important to test Offprint requests to: P. Lapalus Results Human retina micro-autoradiographs These are presented in Fig. 1 and 2 for piribedil and $584, and show histological sections (bright fields) and labelled sections (dark fields), with the silver grains vis- ualizing the binding sites. These micro-autoradiographs confirm the presence of D1 and D2 receptors in human retina. Binding sites were mainly localized in outer and inner plexiform layers. Piribedil binds to D2 receptors while its metabolite ($584) to D1 receptors. Pharmacokinetic studies All ocular tissue levels (expressed as a percentage of in- stilled dose at 8 h after application) are presented in Fig. 3. Specific evolution of chorio-retina levels are presented in Fig. 4. The absorption of piribedil was rapid. Con- junctivae showed a high concentration of radioactivity at early time-points. In ocular tissues, piribedil showed a rapid penetration, and a concentration gradient was es- tablished with the anterior segment being superior to the