Eugenii Rabiner

Further evaluation of [11C]MP-10 as a radiotracer for phosphodiesterase 10A: PET imaging study in rhesus monkeys and brain tissue metabolite analysis.

[11C]MP‐10 is a potent and specific PET tracer previously shown to be suitable for imaging the phosphodiesterase 10A (PDE10A) in baboons with reversible kinetics and high specific binding. However, another report indicated that [11C]MP‐10 displayed seemingly irreversible kinetics in rhesus monkeys, potentially due to the presence of a radiolabeled metabolite capable of penetrating the blood‐brain‐barrier (BBB) into the brain. This study was designed to address the discrepancies between the species by re‐evaluating [11C]MP‐10 in vivo in rhesus monkey with baseline scans to assess tissue uptake kinetics and self‐blocking scans with unlabeled MP‐10 to determine binding specificity. Ex vivo studies with one rhesus monkey and 4 Sprague‐Dawley rats were also performed to investigate the presence of radiolabeled metabolites in the brain. Our results indicated that [11C]MP‐10 displayed reversible uptake kinetics in rhesus monkeys, albeit slower than in baboons. Administration of unlabeled MP‐10 reduced the binding of [11C]MP‐10 in a dose‐dependent manner in all brain regions including the cerebellum. Consequently, the cerebellum appeared not to be a suitable reference tissue in rhesus monkeys. Regional volume of distribution (VT) was mostly reliably derived with the multilinear analysis (MA1) method. In ex vivo studies in the monkey and rats only negligible amount of radiometabolites was seen in the brain of either species. In summary, results from the present study strongly support the suitability of [11C]MP‐10 as a radiotracer for PET imaging and quantification of PDE10A in nonhuman primates. Synapse 69:86–95, 2015.

Chapter Eleven – Imaging the Dopamine D3 Receptor In Vivo

The dopamine D3 receptor has been recognized as a distinct entity from the molecularly similar dopamine D2 receptor, functionally and in anatomical distribution, since 1990, but has not been amenable to characterization of its in vivo properties with imaging techniques for most of that time due to the absence of selective radiotracers. The positron emission tomography radiotracer [11C]-(+)-PHNO, originally developed in 2005 for its D2/D3 agonist properties, has recently been shown to be a strongly D3-preferring tracer that nonetheless binds nontrivially to D2 receptors as well. While the selectivity properties of this tracer present methodological challenges for pharmacokinetic quantification, [11C]-(+)-PHNO imaging has, for the first time, made D3 receptor imaging in the living human brain possible, and several interesting results in neuropsychiatric populations have already begun to emerge. In this chapter, we review the methodological developments of D3 receptor imaging with [11C]-(+)-PHNO in both preclinical species and humans, as well as imaging studies that have been performed in patient populations.