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Parametric PET Imaging of 5HT_2A Receptor Distribution with ¹⁸F-Setoperone in the Normal Human Neocortex

INSERM U320, Cyceron, University of Caen, CEA DSV/DRM, Caen, France

Correspondence: For correspondence or reprints contact: Jean-Claude Baron, MD, INSERM U320-Cyceron, BP 5229, Bd Becquerel, 14074 Caen, France.

ABSTRACT

Because of 5HT_2A receptor's (5HT_2AR) putative role in several neuropsychiatric diseases, studying it in vivo is an important goal. ¹⁸F-setoperone is a well-validated and widely used PET radioligand for the study of neocortical 5HT_2AR. We have previously developed and validated in baboons a method to generate parametric maps of the binding potential (i.e., the k₃-to-k₄ ratio) on a pixel-by-pixel basis, based on a single-dose tracer amount dynamic ¹⁸F-setoperone PET paradigm, and with the receptor-poor cerebellum as reference structure. However, previous semiquantitative PET human studies suggested that nonspecific (NS) binding in the neocortex might not be identical to that in the cerebellum. Methods: As a first step in the development of k₃:k₄ parametric mapping in humans, we therefore estimated directly the NS binding of ¹⁸F-setoperone in the neocortex of four young healthy volunteers who were studied with PET both before and after 2 wk of daily therapeutic oral doses of sertindole, an atypical neuroleptic possessing strong 5HT_2AR antagonistic activity. Results: Visual analysis of the dynamic PET data obtained over 120 min confirmed that virtually full receptor saturation had indeed been achieved; however, the late neocortical time-activity curves (TACs) progressively fell to lower uptake values than corresponding cerebellar TACs and could not be fitted according to a four-compartment (four-Cpt) nonlinear model, indicating lack of specific binding. The cerebellum TACs for both the control and the challenge conditions, as well as the challenge neocortical TACs, were fitted according to three-Cpt modeling, providing the k₅/k₆ ratio and in turn the f₂ fraction for both structures. Despite the small sample of only four subjects, the f₂ fraction for the neocortex was significantly larger (i.e., NS binding was smaller) than that estimated for the cerebellum. This allowed us to determine the k₃-to-k₄ ratio for the control neocortex using the challenge neocortex as reference structure, that is, without using the cerebellum at all. This "assumption-free" approach was also successfully used to generate k₃:k₄ maps for these four subjects, which showed highest values for the temporal cortex. Conclusion: This study shows that, for every new PET or SPECT radioligand and when estimation of specific binding is based on a reference structure, it is important to determine the uniformity of nonspecific binding before proceeding with human investigations.

Key Words: PET • serotonin • modeling • nonspecific binding

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