0770 Science Center Drive

San Diego, CA, United States

0770 Science Center Drive

San Diego, CA, United States
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Collier T.L.,Harvard University | Collier T.L.,Advion Inc. | Normandin M.D.,Harvard University | Stephenson N.A.,Harvard University | And 14 more authors.
Nature Communications | Year: 2017

Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11 C- and 18 F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11 C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability. © The Author(s) 2017.


Braganza J.F.,0770 Science Center Drive | Bernier L.,0770 Science Center Drive | Botrous I.,0770 Science Center Drive | Collins M.R.,0770 Science Center Drive | And 8 more authors.
Tetrahedron Letters | Year: 2015

An efficient synthesis of 6-substituted-pyrazolo[1,5-a]pyridines via an intramolecular cyclization of 1-amino-2-triethyl-silanylethynyl-pyridinium salts has been developed. The cyclization reaction proceeds in the presence of catalytic silver(I) and gold(III) salts to give 2-silyl pyrazolo[1,5-a]pyridines; while the use of stoichiometric silver(I) fluoride predominantly gives the des-silyl heterocycles. © 2015 Elsevier Ltd. All rights reserved.

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