Radiosynthesis and evaluation of new α1-adrenoceptor antagonists as PET radioligands for brain imaging

Introduction: Evaluation of the α1-adrenoceptors in relation to brain pathophysiology and drug treatment has been hindered by lack of α1-adrenoceptor specific radioligands with sufficient brain exposure. Our aim was to develop an α1-adrenoceptor specific PET radioligand for brain imaging.

Methods: Two sertindole analogues 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-[(11)C]methylpiperidin-4-yl)-1H-indole [(11)C]3 and 1-(4-fluorophenyl)-3-(1-[(11)C]methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole ([(11)C]Lu AA27122) [(11)C]4 were synthesized and evaluated as α1-adrenoceptor PET radioligands in cynomolgus monkey. Compounds 3 and 4 were selected due to their promising in vitro preclinical profile; high affinity and selectivity for the α1-adrenoceptor, favourable blood brain barrier permeability rates in Caco-2 monolayers and promising brain tissue/plasma ratio, assessed by equilibrium dialysis of free fraction in plasma and brain homogenate.

Results: Compounds [(11)C]3 and [(11)C]4 were synthesized from their desmethyl piperidine precursors with high specific radioactivity (>370 GBq/μmol) using [(11)C]methyl iodide. The 1,2,4-triazole analogue [(11)C]3 exhibited poor brain uptake, but the corresponding pyrimidyl analogue [(11)C]4 exhibited high brain exposure and binding in α1-adrenoceptor rich brain regions. However, the binding could not be inhibited by pretreatment with prazosin (0.1 mg/kg and 0.3 mg/kg). The results were extended by autoradiography of [(11)C]4 binding in human brain sections and competition with antagonists from different structural families, revealing that only a minor portion of the observed binding of [(11)C]4 in brain was α1-adrenoceptor specific.

Conclusion: Though [(11)C]3 and [(11)C]4 proved not suitable as PET radioligands, the study provided further understanding of structural features influencing brain exposure of the chemical class of compounds related to the antipsychotic drug sertindole. It provided valuable insight in the delicacy of blood brain barrier penetration for structurally related compounds and underlines the importance for improved protocols for evaluation of brain penetration of future PET ligands.