Ga-Lai Law

Owing to safety concerns associated with previous gadolinium‐based magnetic resonance imaging (MRI) agents, pyclen‐based Gd chelates are emerging as promising alternatives. However, the development of pyclen‐based chelators has been hindered by synthetic challenges. In this work, we report two new pyclen‐based chelators featuring α ‐aryl‐substituents on two of the acetate arms. Using the Petasis reaction, two lanthanide chelators 3a and 3b were synthesized in just two steps from pyclen. 3a‐Gd exhibits superior coordination stability and relaxivity compared to previously reported Gd ³⁺ chelates of comparable molecular weight. It also has low cytotoxicity and produces a strong, long‐lasting in vivo MRI signal, enabling real‐time monitoring of tissues/organs, as demonstrated in heart, liver, and kidney imaging of mice. Additionally, the chelator also shows improved coordination kinetics for In ³⁺ , Tb ³⁺ , Lu ³⁺ , and Y ³⁺ , highlighting its potential for the development of a new class of next‐generation radiopharmaceuticals.

Owing to safety concerns associated with previous gadolinium‐based magnetic resonance imaging (MRI) agents, pyclen‐based Gd chelates are emerging as promising alternatives. However, the development of pyclen‐based chelators has been hindered by synthetic challenges. In this work, we report two new pyclen‐based chelators featuring α ‐aryl‐substituents on two of the acetate arms. Using the Petasis reaction, two lanthanide chelators 3a and 3b were synthesized in just two steps from pyclen. 3a‐Gd exhibits superior coordination stability and relaxivity compared to previously reported Gd ³⁺ chelates of comparable molecular weight. It also has low cytotoxicity and produces a strong, long‐lasting in vivo MRI signal, enabling real‐time monitoring of tissues/organs, as demonstrated in heart, liver, and kidney imaging of mice. Additionally, the chelator also shows improved coordination kinetics for In ³⁺ , Tb ³⁺ , Lu ³⁺ , and Y ³⁺ , highlighting its potential for the development of a new class of next‐generation radiopharmaceuticals.

In line with the Food and Drug Administration's (FDA’s) initiative to reduce, refine, and potentially replace animal testing in drug development through New Approach Methodologies, including toxicity testing, cancer organoids are emerging as human-relevant platforms for preclinical drug screening. By enabling direct, quantitative multiplex imaging of multiple protein targets in cell-line-derived organoids, our lanthanide imaging toolkit (LIT) extends analysis from conventional monolayer cultures to physiologically relevant three-dimensional models and offers a scalable tool for mechanistic studies, drug screening, and preclinical development with reduced reliance on animals.

Conspectus: Macrocyclic chelators have become an indispensable part of the field of molecular imaging due to their ability to form highly stable complexes with various metal ions for diverse diagnostic and therapeutic applications. Among them, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), which serves as a gold standard in both stability and versatility, is extensively utilized in clinical contexts as contrast agents for a series of imaging modalities, including MRI (magnetic resonance imaging), PET (positron emission tomography), SPECT (single-photon emission computed tomography), and optical imaging. Despite its advantageous properties, in certain cases, DOTA still has limitations to be solved, such as slow radiolabeling kinetics and possible in vivo decomplexation, which have led to increased research interest in structural modifications of the DOTA ligand. To date, the most popular design strategy for DOTA analogues focuses on the modification of pendant arms, which can be simply achieved through the N-derivatization of the tetraaza macrocycle. Another strategy is to modify the macrocyclic ring structure, with the most successful example being the macrocycle pyclen, which contains a pyridine moiety. In 2022, pyclen-based Gd3+ complex gadopiclenol was approved by the U.S. FDA (United States Food and Drug Administration) as a next-generation MRI contrast agent for clinical use. However, reported studies on similar structural modifications of macrocyclic rings are relatively rare, as this requires the redesign of synthetic procedures that can be highly complicated. In this Account, we discuss our design strategies of various macrocyclic chelators with chiral substituents on the macrocyclic ring for different biomedical imaging applications. We start with structural modifications to the frequently used DOTA chelator through the introduction of four symmetrical chiral substituents on its macrocyclic backbone. Results of NMR studies confirmed that the incorporated chiral substituents can prevent the interconversion between two TSAP/SAP regioisomers formed in the complexation process of DOTA with lanthanides. The chiral substituents also provide increased ligand rigidity and can enhance the coordination geometry for better encapsulation of the metal, preventing possible dechelation and transmetalation, thereby achieving higher coordination stability. A series of DOTA analogues with different chiral substituents were studied, and we have revealed that the TSAP/SAP isomeric ratios and pharmacokinetics of chiral DOTA varied with the steric hindrance and polarity of attached chiral groups. In particular, the Gd3+ complexes of chiral DOTAs with symmetric aliphatic groups exhibit enhanced relaxivity over that of achiral DOTA, making them ideal contrast agents for MR imaging. Through the subsequent optimization of introduced chiral groups, various improved chelators were then developed for photoluminescence or for MRI. Next, we focused on further pendant arm modifications of these chiral DOTA platforms. Multiple functionalized pendant arms were attached to the chiral macrocycle as chromophores or targeting vectors, resulting in versatile chiral bifunctional chelators for targeted circularly polarized luminescence (CPL), PET/SPECT, and radiotherapy applications. Moreover, our chiral modifications are not limited to the 12-membered DOTA macrocycle. Recently, we broadened our design strategy to alter the macrocyclic ring sizes, an approach with relatively few literature examples. The chiral analogues of 9-membered NOTA and 10-membered DETA systems were synthesized for 68Ga radiolabeling, with the influence of cavity sizes and positions of chiral substitution investigated. Follow-up studies will go deeper into the metal ion selectivity effects of differently sized chiral macrocycles to pave the way for future designs on novel macrocyclic chelators.

A four-pronged anchorage is presented to decorate gold nanoparticles with chiral Gd complexes, restricting rotational freedom to yield a hybrid MRI/CT contrast probe with enhanced relaxivity for multimodal imaging.

⁶⁸Ga-labeled macrocyclic ligands have been extensively studied and used for positron emission tomography (PET) imaging. Compared with 12-membered DOTA derivatives, NOTA-based chelators with 9-membered macrocyclic rings exhibit more advantageous coordination stability for Ga³⁺ ions. However, studies of the 10-membered DETA macrocycle are still quite limited. Here, we present the synthesis of four different-sized chiral macrocyclic ligands L1–L4, followed by radiolabeling and stability studies to reveal the influence of ring size and chiral substituents on Ga³⁺ chelation. In the ⁶⁸Ga radiolabeling experiments, chiral NOTA L1 exhibits the highest radiochemical yield of 99% at 25 °C. While for the chiral DETA L2/L3 and the chiral DOTA L4, their radiolabeling efficiencies are inferior at room temperature, but remarkable improvements were observed at higher temperatures. L1–L4 all exhibit superior Ga³⁺ coordination stability than their achiral counterparts, while the chiral DETA L2 with an α-methyl group shows a slightly better performance than its β-analogue L3. Serum stability tests and kinetic studies under acid and alkaline conditions were conducted, highlighting the favorable kinetic inertness of these chiral ligands for potential ⁶⁸Ga-labeled PET imaging applications.

Two new ligands (L^meta: meta-tris-β-diketonate and L^para: para-tris-β-diketonate) with meta and para orientations of coordinating bidentate β-diketonate units were synthesized in order to investigate their supramolecular formation behavior. When chiral (R)- or (S)-BINAPO (L^R/S) was used as a chiral inducer, trinuclear triple-decker metallocyclophane, Eu₃(L^meta)₃(L^R/S)₃, was formed from L^meta, whereas a tetranuclear tetrahedral cage Eu₄(L^para)₄(L^R/S)₄ was formed with L^para. The X-ray crystal of Eu₃(L^meta)₃(L^S)₃ shows that all three Eu centers possess the same configuration, hence resulting in homochiral ΔΔΔ assembly. The triple-decker exhibited a longer luminescence lifetime (∼0.98 ms vs ∼0.74 ms) and higher quantum yields (∼66% vs ∼50%) than the tetrahedral cage. Moreover, chiroptical properties were observed for a lanthanide triple-decker metallocyclophane: Mirror-image circular dichroism of chiral Eu₃(L^meta)₃(L^R/S)₃ or Eu₄(L^para)₄(L^R/S)₄ discloses their enantiomeric behavior and chiral transmission from (R)- or (S)-BINAPO moiety to achiral L^meta and L^para. Furthermore, their circularly polarized luminescence indicated that the |g_lum| can reach 0.13 for the triple-decker metallocyclophane and 0.16 for the tetrahedral cage.

Radiopharmaceuticals rely on radioactive isotopes for diagnosis and therapy, particularly in positron emission tomography (PET), but removing excess radiometals to ensure biosafety and imaging quality is a time-consuming process that causes radiotracer decay, while organic eluents might cause health hazards. In this study, we present a solid-phase material, NOTA-resin, which enables efficient radiometal removal (clearance rate >97% in 4 min) in a single step, at room temperature, and without organic solvents. Furthermore, we have validated the practicability of NOTA-resin in tumor-bearing mice models, demonstrating its compatibility with commercial radiotracers without adverse effects on tumor targeting and PET imaging quality while significantly shortening processing times, saving resources, and reducing waste.

1,4,7‐triazacyclononane (TACN) derivatives play important roles in various metal‐based biomedical applications. However, the unmanageable functionalization of TACN remains a long‐standing challenge to yield useful partially substituted building blocks. Herein, by utilizing nitrobenzoxadiazole (NBD) as a thiol‐liable protecting group for secondary amines, a bis‐NBD‐substituted TACN was obtained as the first example in the preparation of partially substituted TACN without strict stoichiometric control and column chromatography. Upon facile deprotection of NBD using solid‐phase synthesis, a series of TACN‐peptide conjugates with different bioactive peptides and chelating units were derivatized from the TACN building block, demonstrating the potential widespread application of this work.

Lanthanide–tetrazine complexes were synthesised and evaluated via optical spectroscopy and relaxivity. A bio-orthogonal click reaction with a cyclic-RGD-peptide was successful and the resulting Gd complex demonstrated enhanced relaxivity.