Evaluation of [¹⁸F]AMC-15, [¹⁸F]FPr-AMC-13 and [¹⁸F]FEt-AMC-13 as candidate dopamine D_2/3-agonist radioligands for PET

Objectives D_2/3-agonist PET tracers are more sensitive to endogenous dopamine levels than D_2/3-antagonists [1] and offer, at least in theory, the opportunity to study the high-affinity state of D_2/3 in vivo [2]. Here we report the in vitro and preliminary in vivo evaluation of several ¹⁸F-labeled D_2/3-agonist tracers based on a scaffold not used for tracer development before.

Methods Specific-to-total binding ratios were measured by in vitro autoradiography in rat brain slices containing both striatum and cerebellum. In vivo evaluation was conducted in Sprague-Dawley rats using a microPET Focus 220 camera. Binding potential values (BP_ND) were obtained from the SRTM model using cerebellum as reference region.

Results Based on the results of in vitro receptor binding and functional assays two compounds, AMC-15 and FBu-AMC-13, were selected for ¹⁸F-labeling. Less lipophilic homologues of [¹⁸F]FBu-AMC-13 - [¹⁸F]FPr-AMC-13 and [¹⁸F]FEt-AMC-13 - were also prepared for assessment. In rat brain slices the D_2/3-specific component of total striatal binding was 36% for [¹⁸F]AMC-15, 8% for [¹⁸F]FBu-AMC-13, 42% for [¹⁸F]FPr-AMC-13 and 69% for [¹⁸F]FEt-AMC-13. In vivo maximum brain uptake reached 0.1%ID for [¹⁸F]AMC-15, 1.7%ID for [¹⁸F]FPr-AMC-13 and 0.9%ID for [¹⁸F]FEt-AMC-13. Of the three tracers, only [¹⁸F]FEt-AMC-13 showed preferential uptake in the striatum that could be decreased by pre-treatment with the D_2/3-antagonist raclopride (BP_ND 0.50±0.04 in controls vs 0.38±0.09 in raclopride pre-treated rats).

Conclusions [¹⁸F]FEt-AMC-13 appears to bind specifically to D_2/3 in living rat brain. However, this tracer’s signal-to-noise ratio is too low to warrant further use.

Research Support This research was financially supported by the Dutch Technology Foundation (STW), project number 10127.