Radiosynthesis and Evaluation of [11C]HD-800, a High Affinity Brain Penetrant PET Tracer for Imaging MicrotubulesClick to copy article linkArticle link copied!
- Kiran Kumar Solingapuram SaiKiran Kumar Solingapuram SaiDepartment of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, United StatesMore by Kiran Kumar Solingapuram Sai
- Jaya PrabhakaranJaya PrabhakaranMolecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, United StatesDepartment of Psychiatry, Columbia University Medical Center, New York, United StatesMore by Jaya Prabhakaran
- Gayathri RamanathanGayathri RamanathanDepartment of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, United StatesMore by Gayathri Ramanathan
- Stephanie RideoutStephanie RideoutDepartment of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, United StatesMore by Stephanie Rideout
- Christopher WhitlowChristopher WhitlowDepartment of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, United StatesMore by Christopher Whitlow
- Akiva MintzAkiva MintzDepartment of Radiology, Columbia University Medical Center, New York, United StatesMore by Akiva Mintz
- J. John MannJ. John MannMolecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, United StatesDepartment of Psychiatry, Columbia University Medical Center, New York, United StatesDepartment of Radiology, Columbia University Medical Center, New York, United StatesMore by J. John Mann
- J. S. Dileep Kumar*J. S. Dileep Kumar* Fax: 646-774-7521; Tel: 646-774-7522; E-mail: [email protected]Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, United StatesMore by J. S. Dileep Kumar
Abstract

Microtubules (MTs) are highly abundant throughout the cytoskeleton, and their dysfunction is implicated in the pathogenesis of malignancies, various neurodegenerative disorders, and brain injuries. Validated radiotracers reported so far for MTs are [11C]paclitaxel, [18F]fluoropaclitaxel, and [11C]docetaxel; however, they are well-characterized substrates of efflux transporters and consequently have poor uptake into the brain due to minimal blood brain barrier (BBB) penetration. PET imaging of MT expression requires radiolabeled BBB penetrating MT ligands, and it may offer a direct and more sensitive approach for early diagnosis, monitoring disease progression, and treatment effects in brain diseases and assessing the clinical potential of targeted therapeutics and treatments. We have identified N-(4-methoxyphenyl)-N-5-dimethylfuro[2,3-d]pyrimidin-4-amine (HD-800) as a high affinity and selective colchicine site tubuline inhibitor amenable to radiolabel with C-11, a positron emitting isotope. HD-800 and desmethyl-HD-800 were synthesized in one step with 75% and 80% yields respectively from commercial synthons. The radiosynthesis of [11C]HD-800 was achieved in 45 ± 5% yield at EOS. Ex vivo biodistribution binding data of [11C]HD-800 indicate that the radioligand penetrated the BBB and it was retained in brain with 75% specific binding. Apart from the brain, specific binding was observed in muscle (55%), heart (50%), lungs (43%), blood (37%), and pancreas (30%). MicroPET imaging in mice showed excellent binding in brain that was blocked by preadministration of unlabeled HD-800 and a colchicine site binding MT ligand MPC-6827. The above results indicate that [11C]HD-800 may be a suitable PET ligand for the in vivo quantification of MT inside and outside the brain.
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