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Validation of the Transporter Ligand Cyanoimipramine as a Marker of Serotonin Innervation Density in Brain

Département de Médecine Nucléaire, Hôpital Notre-Dame and Département de Pathologie et Centre de Recherche en Sciences Neurologiques, Université de Montréal, Montréal, Canada

Correspondence: For correspondence or reprints contact: L. Descarries, MD, Département de Pathologie, Université de Montréal, CP 6128, Succursale A, Montréal, Québec, Canada H3C 3J7.

ABSTRACT

Radiolabeled ligands of monoamine transporters have already been used to visualize cerebral monoamine innervation by tissue autoradiography and by PET or SPECT in vivo. Methods: A sampling technique was developed to allow for both the autoradiographic counting of serotonin (5-HT) axonal varicosities, labeled by uptake and storage of [³H]5-HT, and the measurement of the binding of [³H]cyanoimipramine ([³H]CYI), a specific 5-HT transporter ligand, in adjacent slices of adult rat neostriatum. The experiments were conducted in normal, decreased (after 5,7-dihydroxytryptamine lesions in adults) or increased (after 6-hydroxydopamine lesions in neonates) states of neostriatal 5-HT innervation. Results: In normal tissue, the regional density of [³H]CYI binding faithfully reproduced rostrocaudal variations in the number of [³H]5-HT-labeled axonal varicosities. Pairs of values from all three experimental groups showed a highly significant linear correlation (r = 0.93) between the density of [³H]CYI binding and the number of 5-HT varicosities per cubic millimeter of tissue. The intercept of the regression line was close to zero; this confirmed the selectivity of the ligand. Conclusion: Under drug-free conditions, specific [³H]CYI binding is a good quantitative index of 5-HT innervation density in brain tissue and is not significantly up- or downregulated on 5-HT denervation or hyperinnervation. When it is adequately labeled, such a ligand might therefore be appropriate to quantify regional 5-HT innervation in vivo by PET or SPECT. The present approach should also be useful to select ligands to quantify 5-HT and monoamine systems.

Key Words: monoamines • terminals • monoamine innervation, quantification of • PET • SPECT

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