Dana Q. M. Soika

Abstract 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.

Abstract Concentration‐dependent increases in relaxivity (r1) were found to be induced by self‐assembly when Fmoc is adjacent to tryptophan in peptide‐based MRI contrast agents featuring Gd‐DOTA. A series of di‐ and tri‐peptides were synthesized to test the effect of ionic strength, N‐terminal substituent, peptide length, net charge, and relative location of Fmoc and tryptophan on r1 and critical aggregation concentration (CAC) at 1.0 Tesla. Compared to nominal r1 values of 3.5–7.4 mM −1 s −1 per Gd(III), r1 values increased dramatically to 13.2–16.9 mM −1 s −1 per Gd(III) upon self‐assembly, with CACs between 0.22 and 2.59 mM when tested in H2O or PBS. When tested in fetal bovine serum (FBS), the compounds maintained high r1 values of 11.2‐13.0 mM −1 s −1 , but had dramatically lower CAC values below 25 μM. These findings guided the synthesis of two targeted, high‐relaxivity MRI contrast agents that contained PSMA‐binding ligand, DCL. Their r1 values in H2O or PBS increased from 5.9–7.4 mM −1 s −1 to 13.5–14.8 mM −1 s −1 with CAC values of 1.65–2.70 mM. In FBS, their r1 values were found to be 11.2–11.9 mM −1 s −1 , with CAC values below 25 μM. By the conjugation of targeting agents in the last step of synthesis, a broadly applicable route to targeted, high‐relaxivity MRI contrast agents is offered.

Targeted molecular imaging agents (TMIAs) are emerging as important tools for diagnosing cancer and other diseases. In their Communication on page 13848 ff., H. F. Schmitthenner et al. describe a modular approach to TMIA synthesis by introducing a metal atom early on to form an imaging module for MRI or PET. This is coupled with a targeting module in a convergent step to form a selective imaging agent for prostate cancer. By grasping a branch, the colorful toucan emulates the color-matched TMIA by targeting and lighting up the location of a tree in the forest.