Modular Synthesis of DOTA‐Metal‐Based PSMA‐Targeted Imaging Agents for MRI and PET of Prostate Cancer

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, La3+ or Ce3+, can be used as placeholders in DOTA during the synthesis, then transmetalated in mild acid by Cu2+, Ga3+, In3+, and Y3+, 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.

Modular Synthesis of Peptide-Based Single- and Multimodal Targeted Molecular Imaging Agents

“…While the chelation by Cu 2+ was complete in method B, La 3+ was found to complete with Ga 3+ for re-metalation under these conditions. To solve this and ensure complete transmetalation, a method was devised to adhere the demetalated TMIA in mild acid to a C-18 solid phase extraction (SPE) column, washing away the La 3+ , then treating the column with a 5 mM aqueous solution of Ga 3+ , and eluting the pure product with an acetonitrile–water gradient. , …”

“…Of the TMIAs shown in Table , an example of an easily constructed single-modal TMIA ( 7 ) prepared by the method in Scheme , containing the chelated Gd–DOTA with SMCC linker, is shown in Figure . In an earlier publication, we described a related application of the modular method to single-modal TMIAs for MRI and PET of PCa, similarly targeting PSMA by the use of DSS–DCL. ,,− …”

“…77 The resulting modules may be coupled using standard Fmoc deprotection followed by coupling to a targeting system or to the C-terminal acid of a second Fmocprotected imaging module as shown in Scheme 2. 69,77 Modules containing NIR dyes were synthesized as shown in Figure 2. Single-modal TMIAs for the OMI and PAI of prostate cancer (PCa) based on dye modules were described earlier by the Pomper group.…”

“…74−76 For modules containing chelated metals, a three-step procedure described earlier 69 was replaced by a one-pot procedure shown in Figure 1. 77 The resulting modules may be coupled using standard Fmoc deprotection followed by coupling to a targeting system or to the C-terminal acid of a second Fmocprotected imaging module as shown in Scheme 2. 69,77 Modules containing NIR dyes were synthesized as shown in Figure 2.…”

Cesium Carbonate Catalyzed Oxa‐Michael Addition of Oximes to Acrylonitrile

“…Full Papers doi.org/10.1002/slct.202100924 higher amount of the Z product in the reaction mixture compared to reactions without lanthanide salt (Table 2, entries b, d, f). To ensure a defined interaction between the Lewis acidic cerium complex and the oxime we used a cerium (III) 1,4,7-10-tetraazacyclododecan-1,4,7,10-tetraacetic acid (DOTA) [19,21] complex. Mixing the oxime and the cerium complex in presence of the base results in a slight yellow colour (Figure 2).…”