Synthesis and PET evaluation of the translocator protein (18 kDa) (T.S.P.O.) ligand [11C]D.P.A.-715 in rat and non-human primate

The translocator protein (18 kDa) (T.S.P.O.), formerly known as the peripheral benzodiazepine receptor (P.B.R.), is over expressed upon micro-glial activation. This study involved the evaluation of the pyrazolo-pyrimidine D.P.A.-715 (T.S.P.O. Ki = 16.4 nM) in behavioural studies and the radiolabelled form, [11C]D.P.A.-715, in healthy non-human primate and A.M.P.A.-lesioned rats as a model of activated micro-glia using PET. The in vivo anxiolytic effects of D.P.A.-715 were assessed using the social interaction test which represents social anxiety in humans. [11C]D.P.A.-715 was prepared using [11C]CH3I as the labelling intermediate from the phenolic precursor of D.P.A.-715 using T.B.A.H. and D.M.F. followed by H.P.L.C.. The non-human primate distribution studies were performed using a clinical PET scanner, and A.M.P.A.-lesioned rats using micro PET. Blocking studies were conducted using P.K.11195 (5 mg/kg).In the social interaction test a significant overall effect for the duration of time spent in general investigation, adjacent lying and rearing was observed. Post hoc analysis revealed a significantly greater time spent in general investigation and adjacent lying in the 20 mg/kg D.P.A.-715 treatment group compared to vehicle treated rats. The average non-decay corrected radiochemical yield of [11C]D.P.A.-715 was 0.27 ± 0.05% with an average specific activity of 16.32 ± 4.01 GBq/mmol. The PET distribution studies revealed poor brain uptake. Pre-treatment with P.K.1195 resulted in no change of in the uptake of the radioligand, which suggests that brain uptake is representative of non-specific binding. In agreement with these results, the brain uptake in the A.M.P.A. lesioned model, depicted no significant differences between the lesioned striatum and the non-lesioned contralateral striatum. Although D.P.A.-715 does possess anxiolytic properties in vivo, [11C]D.P.A.-715 does not possess the required properties for further development as a PET radioligand for imaging the T.S.P.O. (18 kDa). (N.C.)