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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.

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