225Ac-based radiotheranostics targeting prostate-specific membrane antigen (PSMA) has induced impressive responses in patients with metastatic castration-resistant prostate cancer. To enhance the therapeutic effects of radioligands labeled with 225Ac (half-life: 10 days), a radioligand that shows longer tumor retention would be useful. Here, we designed and synthesized a straight-chain PSMA-targeting radioligand, PSMA–DA1, which includes an (iodophenyl)­butyric acid derivative as an albumin binder (ALB). We performed preclinical evaluations of PSMA–DA1 as a tool for PSMA-targeting radiotheranostics using 111In, 90Y, and 225Ac. [111In]­In-PSMA–DA1 demonstrated significantly greater tumor uptake and retention than a corresponding non-ALB-conjugated compound. In mice, single-photon emission computed tomography performed with [111In]­In-PSMA–DA1 produced clear tumor images, and the administration of [90Y]­Y-PSMA–DA1 or [225Ac]­Ac-PSMA–DA1 inhibited tumor growth. [225Ac]­Ac-PSMA–DA1 had antitumor effects in mice at a lower radioactivity level than [225Ac]­Ac-PSMA-617, which has been reported to be clinically useful. These results indicate that PSMA–DA1 may be a useful PSMA-targeting radiotheranostic agent.

Noninvasive imaging of tau aggregates with a positron emission tomography (PET) tracer is useful for the diagnosis and staging of Alzheimer's disease (AD). Recently, we found that benzimidazopyridine (BIP) is an attractive scaffold for developing PET and single photon computed emission tomography tracers targeting tau aggregates. In this study, we designed and synthesized five novel 18 F-labeled compounds with various substituted groups or atoms at the 7-position of the BIP scaffold. In in vitro autoradiographic studies, all 18 F-labeled BIP derivatives selectively bound to tau aggregates deposited in AD brain sections. On the other hand, the initial brain uptake of these compounds was affected by the type of substituted group or halogen atom introduced into the 7-position of the BIP scaffold. Among these compounds, [ 18 F]Me-BIPF showed the highest brain uptake (6.79% ID/g at 2 min postinjection) and 2 min/60 min ratio (3.59). These results suggest that appropriate introduction of the substituted group or atom into the 7-position of the BIP scaffold may be effective for developing useful tau PET tracers.

Picolinic acid-based metallic chelators, e.g., neunpa and octapa, have attracted much attention as promising scaffolds for radiotheranostic agents, particularly those containing larger α-emitting radiometals. Furthermore, albumin binder (ALB) moieties, which noncovalently bind to albumin, have been utilized to improve the pharmacokinetics of radioligands targeting various biomolecules. In this study, we designed and synthesized novel neunpa and octapa derivatives (Neunpa-2 and Octapa-2, respectively), which contained a prostate-specific membrane antigen (PSMA)-binding moiety (model targeting vector) and an ALB moiety. We evaluated the fundamental properties of these derivatives as radiotheranostic agents using 111In. In a cell-binding assay using LNCaP (PSMA-positive) cells, [111In]­In-Neunpa-2 and [111In]­In-Octapa-2 specifically bound to the LNCaP cells. In addition, a human serum albumin (HSA)-binding assay revealed that [111In]­In-Neunpa-2 and [111In]­In-Octapa-2 exhibited greater binding to HSA than their non-ALB-conjugated counterparts ([111In]­In-Neunpa-1 and [111In]­In-Octapa-1, respectively). A biodistribution assay conducted in LNCaP tumor-bearing mice showed that the introduction of the ALB moiety into the 111In-labeled neunpa and octapa derivatives resulted in markedly enhanced tumor uptake and retention of the radioligands. Furthermore, single-photon emission computed tomography imaging of LNCaP tumor-bearing mice with [111In]­In-Octapa-2 produced tumor images. These results indicate that [111In]­In-Octapa-2 may be a useful PSMA imaging probe and that picolinic acid-based ALB-conjugated radiometallic complexes may be promising candidates as radiotheranostic agents.

The accumulation of hyperphosphorylated tau protein in the brain is regarded as one of the hallmarks of Alzheimer's disease (AD). In vivo imaging of tau aggregates is helpful for diagnosis and monitoring of the progression of AD. In this study, we designed and synthesized novel radioiodinated benzimidazopyrimidine (BIPM) and pyridoimidazopyridine (PIP) derivatives with a monomethylamino, monoethylamino, monopropylamino, or diethylamino group as tau imaging probes for single-photon-emission computed tomography (SPECT). On in vitro autoradiography with AD brain sections, [ 125 I]PIP-NHMe showed the highest selective binding affinity for tau aggregates among the radioiodinated BIPM and PIP derivatives. In a biodistribution study using normal mice, [ 125 I]PIP-NHMe and [ 125 I]PIP-NHEt displayed high initial uptake (6.62 and 6.86% ID/g, respectively, at 2 min postinjection) into and rapid clearance from the brain, with brain 2 min /brain 30 min ratios of 38.9 and 28.6, respectively. These results suggest that [ 123 I]PIP-NHMe may be a novel SPECT probe that is useful for detecting tau aggregates in the AD brain.