In vivo comparison of N-CH vs O-CH radiolabeled microtubule targeted PET ligands.

Altered dynamics of microtubules (MT) are implicated in the pathophysiology of a number of brain diseases. Therefore, radiolabeled MT targeted ligands that can penetrate the blood brain barrier (BBB) may offer a direct and sensitive approach for diagnosis, and assessing the clinical potential of MT targeted therapeutics using PET imaging. We recently reported two BBB penetrating radioligands, [C]MPC-6827 and [C]HD-800 as specific PET ligands for imaging MTs in brain. The major metabolic pathway of the above molecules is anticipated to be via the initial labeling site, O-methyl, compared to the N-methyl group. Herein, we report the radiosynthesis of N-CH-MPC-6827 and N-CH-HD-800 and a comparison of their in vivo binding with the corresponding O-CH analogues using microPET imaging and biodistribution methods. Both O-CH and N-CH labeled MT tracers exhibit high specific binding and brain. The N-CH labeled PET ligands demonstrated similar in vivo binding characteristics compared with the corresponding O-CH labeled tracers, [C]MPC-6827 and [C]HD-800 respectively.