Synthesis and Preclinical Evaluation of Two Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeted Tracers with 2-Nal-Containing PSMA-Targeted Pharmacophore and Pyridine-Based FAP-Targeted Pharmacophore.

Some bispecific radiotracers have been developed to overcome the limitations of monospecific tracers and improve detection sensitivity for heterogeneous tumor lesions. Here, we aim to synthesize two bispecific tracers targeting prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are key markers expressed in prostate cancer. A pyridine-based FAP-targeted ligand was synthesized through multi-step organic synthesis and then connected to the 2-Nal-containing PSMA-targeted motif. The Ki(PSMA) values of Ga-complexed bispecific ligands, Ga-AV01084 and Ga-AV01088, were 11.6 ± 3.25 and 28.7 ± 6.05 nM, respectively, and the IC50(FAP) values of Ga-AV01084 and Ga-AV01088 were 10.9 ± 0.67 and 16.7 ± 1.53 nM, respectively. Both [68Ga]Ga-AV01084 and [68Ga]Ga-AV01088 enabled the visualization of PSMA-expressing LNCaP tumor xenografts and FAP-expressing HEK293T:hFAP tumor xenografts in PET images acquired at 1 h post-injection. However, the tumor uptake values from the bispecific tracers were still lower than those obtained from the monospecific tracers, PSMA-targeted [68Ga]Ga-PSMA-617 and FAP-targeted [68Ga]Ga-AV02070. Further investigations are needed to optimize the selection of linkers and targeted pharmacophores to improve the tumor uptake of bispecific PSMA/FAP tracers for prostate cancer imaging.

Controlling Reactivity and Selectivity in the Mizoroki-Heck Reaction: High Throughput Evaluation of 1,5-Diaza-3,7-diphosphacyclooctane Ligands.

We report a high throughput evaluation of the Mizoroki-Heck reaction of diverse olefin coupling partners. Comparison of different ligands revealed the 1,5-diaza-3,7-diphosphacyclooctane (P2N2) scaffold to be more broadly applicable than common "gold standard" ligands, demonstrating that this family of readily accessible diphosphines has unrecognized potential in organic synthesis. In particular, two structurally related P2N2 ligands were identified to enable the regiodivergent arylation of styrenes. By simply altering the phosphorus substituent from a phenyl to tert-butyl group, both the linear and branched Mizoroki-Heck products can be obtained in high regioisomeric ratios. Experimental and computational mechanistic studies were performed to further probe the origin of selectivity, which suggests that both ligands coordinate to the metal in a similar manner but that rigid positioning of the phosphorus substituent forces contact with the incoming olefin in a π-π interaction (for P-Ph ligands) or with steric clash (for P-tBu ligands), dictating the regiocontrol.

"Lignophines": lignin-based tertiary phosphines with metal-scavenging ability.

Methacrylated lignin was reacted with PH3(g) to prepare a phosphorus rich bio-based polymer containing PH/PH2 functional groups, which were converted to tertiary phosphine units via the phosphane-ene reaction. This represents a straightforward method for the upconversion of low-value biomass waste to useful inorganic polymer with potential utility in metal scavenging applications.