Development of bispecific NT-PSMA heterodimer for prostate cancer imaging: a potential approach to address tumor heterogeneity

Prostate cancer is a heterogeneous disease with poor survival rate at late stage. In this report, a dual targeting PET agent was developed to partially address tumor heterogeneity issue. The heterodimer F-BCN-PSMA-NT was designed to target PSMA and neurotensin receptor1 (NTR1), both of which have demonstrated the great potential in prostate cancer management. The heterodimer was synthesized through the conjugation of Glu-urea-lys(Ahx) (PSMA targeting motif) and NT20.3 (NTR1 targeting motif) to a symmetric trifunctional linker, bearing an azide group for further modification. Radio-labeling was performed using strain promoted azide-alkyne click reaction with high yield. Cell based assays suggested F-BCN-PSMA-NT has comparable or only slightly reduced binding affinity with the corresponding monomers. Small animal PET clearly demonstrated that the heterodimer probe not only has prominent uptake in NTR1 positive/PSMA negative PC-3 tumors (1.4 ± 0.3 %ID/g), but also in the PSMA positive/NTR1 negative LnCap tum...