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. 2020 Jan 15;30(2):126785.
doi: 10.1016/j.bmcl.2019.126785. Epub 2019 Nov 9.

In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands

J S Dileep Kumar  1 , Jaya Prabhakaran  2 , Naresh Damuka  3 , Justin Wayne Hines  4 , Skylar Norman  4 , Meghana Dodda  4 , J John Mann  5 , Akiva Mintz  6 , Kiran Kumar Solingapuram Sai  7
Affiliations

In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands

J S Dileep Kumar et al. Bioorg Med Chem Lett. .

Abstract

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, [11C]MPC-6827 and [11C]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-11CH3-MPC-6827 and N-11CH3-HD-800 and a comparison of their in vivo binding with the corresponding O-11CH3 analogues using microPET imaging and biodistribution methods. Both O-11CH3 and N-11CH3 labeled MT tracers exhibit high specific binding and brain. The N-11CH3 labeled PET ligands demonstrated similar in vivo binding characteristics compared with the corresponding O-11CH3 labeled tracers, [11C]MPC-6827 and [11C]HD-800 respectively.

Keywords: Brain; Microtubule; PET; Radiotracer; Tubulin.

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Conflict of interest statement

Declaration of Competing Interest

J John Mann receives royalties for commercial use of the C-SSRS from the Research Foundation of Mental Hygiene. All other authors delcare that no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Chemical structures of MPC-6827 and HD-800.
Fig. 2.
Fig. 2.
Radiosynthesis of N-11CH3-MPC-6827 and N-11CH3-HD-800.
Fig. 3.
Fig. 3.
Representative 0–30 min summed sagittal and transaxial PET images of O-11CH3-MPC-6827 and N-11CH3-MPC-6827 in mice (A: control O-11CH3-MPC-6827; B: blocking of O-11CH3-MPC-6827 with HD-800; C: Control N-11CH3-MPC-6827; D: Blocking of N-11CH3-MPC-6827 with HD-800).
Fig. 4.
Fig. 4.
Representative 0–30 min summed sagittal and transaxial PET images of O-11CH3-HD-800 and N-11CH3-HD-800 in mice (A: control O-11CH3-HD-800; B: blocking of O-11CH3-HD-800 with MPC-6827; C: Control N-11CH3-HD-800; D: Blocking of N-11CH3-HD-800 with MPC-6827).
Fig. 5.
Fig. 5.
Baseline and blocking time activity curves of O-11CH3-MPC-6827 (A) and N-11CH3-MPC-6827 (B) in mice brain.
Fig. 6.
Fig. 6.
Baseline and blocking time activity curves of O-11CH3-HD-800 (A) and N-11CH3-HD-800 (B) in mice brain.
Fig. 7.
Fig. 7.
Biodistribution O-11CH3-MPC-6827 and N-11CH3-MPC-6827 in mice at 30 min (n = 3) with *p values ≤ 0.05 considered statistically significant.
Fig. 8.
Fig. 8.
Biodistribution O-11CH3-HD-800 and N-11CH3-HD-800 in mice at 30 min (n = 3), with *p values ≤ 0.05 considered statistically significant.
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