RESUMEN
In the field of radiopharmaceutical development targeting cancer, an albumin binder (ALB) is commonly used to improve accumulation of radioligands in tumors because it has high binding affinity for albumin and extends the circulation time of radioligands. The further development of ALB-containing radioligands is also expected to regulate their pharmacokinetics. In this study, we newly designed and synthesized [111In]In-PNT-DA1 derivatives, prostate-specific membrane antigen (PSMA)-targeting radioligands including a functional linker (d-glutamic acid or 4-(aminomethyl)benzoic acid), and evaluated the relationships among the structure, albumin-binding affinity, and pharmacokinetics. These derivatives showed a different binding affinity for albumin by the introduction of a linker. Biodistribution studies revealed that the introduction of a linker affects the pharmacokinetics of each derivative. The biodistribution studies also suggested that moderate albumin-binding affinity enhances the tumor/kidney ratio of the derivative. SPECT imaging using [111In]In-PNT-DA3 with the highest tumor/kidney ratio among [111In]In-PNT-DA1 derivatives led to clear visualization of a PSMA-positive LNCaP tumor. The results suggest that the appropriate introduction of linker entities may be necessary to improve the pharmacokinetics of PSMA-targeting radioligands.
RESUMEN
INTRODUCTION: Prostate-specific membrane antigen (PSMA) is a promising target for treating metastatic castration-resistant prostate cancer. Our previous report presented 111In- or 225Ac-labeled PSMA-NAT-DA1 (PNT-DA1) as a PSMA-targeted ligand. To improve its therapeutic efficiency, PNT-DA1 contains 4-(p-iodophenyl)butyric acid (IPBA), which is known as an albumin binder (ALB) moiety. However, few reports have examined the relationship between the chemical modification of the ALB moiety and pharmacokinetics of PSMA-targeted radioligands. To assess this relationship, we designed, synthesized, and evaluated four [111In]In-PNT-DA1 analogues with ALB moieties different from IPBA. METHODS: The [111In]In-PNT-DA1 analogues were synthesized from their corresponding precursors through ligand substitution reaction. The stability of [111In]In-PNT-DA1 analogues in mouse plasma, their affinity for human serum albumin (HSA), their binding to mouse plasma proteins, and their affinity for PSMA were evaluated in vitro. The tissue distribution profile of the radioligands was assessed in biodistribution studies using LNCaP tumor-bearing nude mice. RESULTS: All [111In]In-PNT-DA1 analogues were obtained at a high radiochemical yield and purity. These analogues were highly stable in mouse plasma after 24 h. The binding affinity for HSA significantly varied among the different ALB moieties. Moreover, high affinity for mouse plasma proteins was observed for all [111In]In-PNT-DA1 analogues compared with their counterparts without an ALB moiety. The affinity for PSMA was comparable for all radioligands. In the biodistribution assay, the pharmacokinetics of [111In]In-PNT-DA1 analogues varied markedly depending on the type of ALB moiety. In particular, tumor area under the curve (AUC) values were increased for radioligands with higher blood retention, while some previous studies reported that compounds with moderate blood retention exhibited the highest tumor AUC values. CONCLUSION: The introduction of an appropriate ALB moiety into the ligand may lead to the development of more useful PSMA-targeted radioligands with higher tumor accumulation.
RESUMEN
OBJECTIVE: The marked success of prostate-specific membrane antigen (PSMA)-targeting radioligands with albumin binder (ALB) is attributed to the improvement of blood retention and tumor accumulation. [111In]In-PNT-DA1, our PSMA-targeting radioligand with ALB, also achieved improved tumor accumulation due to its prolonged blood retention. Although the advantage of ALBs is related to their reversible binding to albumin, the relationship between albumin-binding and tumor accumulation of PSMA-targeting radioligands remains unclear because of the lack of information about radioligands with stronger albumin-binding than ALBs. In this study, we designed and synthesized [111In]In-PNT-DM-HSA, a new radioligand that consists of a PSMA-targeting radioligand covalently bound to albumin. The pharmacokinetics of [111In]In-PNT-DM-HSA was compared with those of [111In]In-PNT-DA1 and [111In]In-PSMA-617, a non-ALB-conjugated radioligand, to evaluate the relationship between albumin-binding and tumor accumulation. METHOD: The [111In]In-PNT-DM-HSA was prepared by incubation of [111In]In-PNT-DM, a PSMA-targeting radioligand including a maleimide group, and human serum albumin (HSA). The ability of [111In]In-PNT-DM-HSA was evaluated by in vitro assays. A biodistribution study using LNCaP tumor-bearing mice was conducted to compare the pharmacokinetics of [111In]In-PNT-DM-HSA, [111In]In-PNT-DA1, and [111In]In-PSMA-617. RESULTS: The [111In]In-PNT-DM-HSA was obtained at a favorable radiochemical yield and high radiochemical purity. In vitro assays revealed that [111In]In-PNT-DM-HSA had fundamental characteristics as a PSMA-targeting radioligand interacting with albumin covalently. In a biodistribution study, [111In]In-PNT-DM-HSA and [111In]In-PNT-DA1 showed higher blood retention than [111In]In-PSMA-617. On the other hand, the tumor accumulation of [111In]In-PNT-DA1 was much higher than [111In]In-PNT-DM-HSA and [111In]In-PSMA-617. CONCLUSIONS: These results indicate that the moderate reversible binding of ALB with albumin, not covalent binding, may play a critical role in enhancing the tumor accumulation of PSMA-targeting radioligands.
Asunto(s)
Antígenos de Superficie , Glutamato Carboxipeptidasa II , Animales , Ratones , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Humanos , Masculino , Ligandos , Línea Celular Tumoral , Distribución Tisular , Unión Proteica , Albúminas/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/diagnóstico por imagen , Albúmina Sérica/metabolismo , Albúmina Sérica/química , Dipéptidos/farmacocinética , Dipéptidos/química , Dipéptidos/metabolismo , Radioisótopos de IndioRESUMEN
Granzyme B is an attractive target as a biomarker for contributing to improve the treatment with immune checkpoint inhibitor (ICI). In this study, we designed novel 111 In-labeled granzyme B-targeting single-photon emission computed tomography (SPECT) imaging probes, [111 In]IDT and [111 In]IDAT. Nonradioactive In-labeled granzyme B-targeting compounds ([nat In]IDT, [nat In]IDAT) showed the affinity for recombinant mouse granzyme B. [111 In]IDT and [111 In]IDAT were obtained with moderate radiochemical yield and high stability in mouse plasma (>95%). In a biodistribution experiment using tumor-bearing mice, [111 In]IDT and [111 In]IDAT showed moderate accumulation in tumor. Ex vivo autoradiography (ARG) indicated that the accumulation of radioactivity in tumor was correlated to expression of granzyme B confirmed by the immunohistochemical staining. These results indicated that [111 In]IDT and [111 In]IDAT showed the basic properties as granzyme B-targeting SPECT probes.