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Modular Synthesis of DOTA‐Metal‐Based PSMA‐Targeted Imaging Agents for MRI and PET of Prostate Cancer
Author(s) -
Schmitthenner Hans F.,
Dobson Damien E.,
Jones Kelsea G.,
Akporji Nnamdi,
Soika Dana Q. M.,
Nastiuk Kent L.,
Hornak Joseph P.
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201903390
Subject(s) - dota , chemistry , chelation , combinatorial chemistry , molecular imaging , imaging agent , biodistribution , pet imaging , gadolinium , mri contrast agent , linker , positron emission tomography , nuclear medicine , in vivo , in vitro , medicine , biochemistry , computer science , organic chemistry , microbiology and biotechnology , biology , operating system
A practical, convergent synthesis of prostate‐specific membrane antigen (PSMA) targeted imaging agents for MRI, PET, and SPECT of prostate cancer has been developed. In this approach, metals chelated to 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) were placed on the side chains of lysine early in the synthesis to form imaging modules. These are coupled to targeting modules, in this case consisting of the PSMA‐binding urea DCL, bonded to an activated linker. The modular approach to targeted molecular imaging agents (TMIAs) offers distinct advantages. By chelating the MRI contrast metal Gd early, it doubles as a protecting group for DOTA. Standard coupling and deprotection steps may be utilized to assemble the modules into peptides, and the need for tri‐ tert ‐butyl protection of DOTA requiring removal by strong acid is averted. This enables mild conjugation of the imaging module to a wide variety of targeting agents in the final step. It was further discovered that two labile metals, La 3+ or Ce 3+ , can be used as placeholders in DOTA during the synthesis, then transmetalated in mild acid by Cu 2+ , Ga 3+ , In 3+ , and Y 3+ , metals used in PET/SPECT. This enables the efficient synthesis of nonradioactive analogues of targeted molecular imaging agents that may be transported or stored until needed. A simple and mild two‐step transmetalation, involving de‐metalation in dilute acid, followed by rapid chelation of the radioactive metal, may be conveniently performed later at the clinic to provide the TMIAs for PET or SPECT.