(R)-NODAGA-PSMA: A Versatile Precursor for Radiometal Labeling and Nuclear Imaging of PSMA-Positive Tumors

PURPOSE: The present study aims at developing and evaluating an urea-based prostate specific membrane antigen (PSMA) inhibitor suitable for labeling with (111)In for SPECT and intraoperative applications as well as (68)Ga and (64)Cu for PET imaging. METHODS: The PSMA-based inhibitor-lysine-urea-glutamate-coupled to the spacer Phe-Phe-D-Lys(suberoyl) and functionalized with the enantiomerically pure prochelator (R)-1-(1-carboxy-3-carbotertbutoxypropyl)-4,7-carbotartbutoxymethyl)-1,4,7-triazacyclononane ((R)-NODAGA(tBu)(3)), to obtain (R)-NODAGA-Phe-Phe-D-Lys(suberoyl)-Lys-urea-Glu (CC34). CC34 was labeled with (111)In, (68)Ga and (64)Cu. The radioconjugates were further evaluated in vitro and in vivo in LNCaP xenografts by biodistribution and PET studies. Biodistribution studies were also performed with (68)Ga-HBED-CC-PSMA (HBED-CC: N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid) and (111)In-PSMA-617 for comparison. RESULTS: (68)Ga-CC34, (64)Cu-CC34, and (111)In-CC34 were prepared in radiochemical purity >95%. (68/nat)Ga-CC34, (64/nat)Cu-CC34, (111/nat)In-CC34, (68/nat)Ga-HBED-CC-PSMA, and (111/nat)In-PSMA-617 exhibited high affinity for the LNCaP cells, with K(d) values of 19.3±2.5 nM, 27.5±2.7 nM, 5.5±0.9 nM, 2.9±0.6 nM and 5.4±0.8 nM, respectively. They revealed comparable internalization profiles with approximately 75% of the total cell associated activity internalized after 3 h of incubation. (68)Ga-CC34 showed very high stability after its administration in mice. Tumor uptake of (68)Ga-CC34 (14.5±2.9% IA/g) in LNCaP xenografts at 1 h p.i. was comparable to (68)Ga-HBED-CC-PSMA (15.8±1.4% IA/g) (P = 0.67). The tumor-to-normal tissue ratios at 1 and 2 h p.i of (68)Ga-CC34 were also comparable to (68)Ga-HBED-CC-PSMA (P>0.05). Tumor uptake of (111)In-CC34 (28.5±2.6% IA/g) at 1 h p.i. was lower than (111)In-PSMA-617 (52.1±6.5% IA/g) (P = 0.02). The acquisition of PET-images with (64)Cu-CC34 at later time points showed wash-out from the kidneys, while tumor uptake still remained relatively high. This resulted in an increased tumor-to-kidney ratio over time. CONCLUSIONS: (68)Ga-CC34 is comparable to (68)Ga-HBED-CC-PSMA in terms of tumor uptake and tumor to normal tissue ratios. (64)Cu-CC34 could enable high contrast imaging of PSMA positive tissues characterized by elevated expression of PSMA or when delayed imaging is required. (64)Cu-CC34 is currently being prepared for clinical translation.