177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy

Preparation of the alpha‐emitting prostate‐specific membrane antigen targeted radioligand [212Pb]Pb‐NG001 for prostate cancer

“…NG001 consists of a highly specific urea‐based PSMA‐binding motif and the TCMC chelator. The linker and binding motif in PSMA inhibitors both influence affinity and internalization, while chelator and linker have high impact on the pharmacokinetic profile regarding tumour and kidney uptake . Also, the conjugation linker for the chelator is of importance.…”

“…Therefore, the human kidney dose cannot be directly extrapolated from mouse kidney uptake with PSMA‐binding ligands. A direct comparison of [ 177 Lu]Lu‐PSMA‐617 and [ 177 Lu]Lu‐PSMA‐I&T in mice demonstrated that [ 177 Lu]Lu‐PSMA‐617 had higher tumour uptake and lower kidney and salivary gland uptake compared with [ 177 Lu]Lu‐PSMA‐I&T . An almost tenfold faster clearance in mice was observed with [ 177 Lu]Lu‐PSMA‐617 .…”

“…The linker and binding motif in PSMA inhibitors both influence affinity and internalization, while chelator and linker have high impact on the pharmacokinetic profile regarding tumour and kidney uptake. 8,30,31,39 Also, the conjugation linker for the chelator is of importance. One improvement of NG001 is that the chelator unit has all four arms free due to the use of a backbone substituted linker instead of using one of the chelator arms for the linking purpose, as in PSMA-617.…”

“…The most studied PSMA ligands for therapeutic use, PSMA‐617 and PSMA‐I&T, have different linkers, while the binding motif (glutamate‐urea moiety) and the chelating moiety (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid [DOTA]) are the same. PSMA‐617 and PSMA‐I&T labelled with the beta emitter 177 Lu ( t 1/2 ≈6.7 days) and MIP‐1095 labelled with the beta emitter 131 I ( t 1/2 ≈8.0 days) have been investigated in preclinical and clinical studies . A recent meta‐analysis of 17 studies demonstrated that RLT with [ 177 Lu]Lu‐PSMA‐617 and [ 177 Lu]Lu‐PSMA‐I&T is an effective treatment for mCRPC with low toxicity .…”

“…PSMA-617 and PSMA-I&T labelled with the beta emitter 177 Lu (t 1/2 ≈6.7 days) and MIP-1095 labelled with the beta emitter 131 I (t 1/2 ≈8.0 days) have been investigated in preclinical and clinical studies. [7][8][9][10][11] A recent meta-analysis of 17 studies demonstrated that RLT with [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T is an effective treatment for mCRPC with low toxicity. 10 However, around 30% of patients do not respond to [ 177 Lu]Lu-PSMA RLT.…”