Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs

Impairment of the ubiquitin proteasome system has been implicated in Parkinson's disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Gottingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400 mu g lactacystin, respectively. Main radioligands included [C-11]-DTBZ (vesicular monoamine transporter type 2) and [C-11]-yohimbine (alpha 2-adrenoceptor). [C-11]-DASB (serotonin transporter) and [C-11]-PK11195 (activated microglia) became available later in the study and we present their results in a smaller subset of animals for information purposes only. Striatal [C-11]-DTBZ binding potentials decreased significantly by 16% after 200 mu g compared to baseline, but the decrease was not sustained after 400 mu g (n = 6). [C-11]-yohimbine volume of distribution increased by 18-25% in the pons, grey matter and the thalamus after 200 mu g, which persisted at 400 mu g (n = 6). In the later subset of minipigs, we observed decreased [C-11]-DASB (n = 5) and increased [C-11]-PK11195 (n = 3) uptake after 200 mu g. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson's disease.