Effects of Linker Modification on Tumor-to-Kidney Contrast of ⁶⁸Ga-Labeled PSMA-Targeted Imaging Probes

Abstract

Ga-PSMA-11 is currently the most popular prostate-specific membrane antigen (PSMA) radioligand used in the clinic to detect prostate cancer and metastases. However, the high uptake of Ga-PSMA-11 in kidneys can create halo-artifacts resulting in lower detection sensitivity for lesions adjacent to the kidneys. In this study, we developed twoGa-labeled PSMA-targeted tracers, Ga-HTK01166 andGa-HTK01167, based on Ga-PSMA-617 with the goal of improving tumor-to-kidney ratio compared toGa-PSMA-11. The 2-naphthylalanine (2-Nal) in PSMA-617 was replaced with 2-indanylglycine (Igl) or 3,3-diphenylalanine (Dip) to synthesize HTK01166 and HTK01167, respectively. Binding affinities ( K) of Ga-PSMA-11, Ga-PSMA-617, Ga-HTK01166, and Ga-HTK01167 to PSMA were 3.13 ± 0.40, 1.23 ± 0.08, 5.74 ± 2.48, and 25.7 ± 9.84 nM, respectively, as determined by in vitro competition binding assays. Ga labeling was performed in HEPES buffer with microwave heating, andGa-labeled PSMA-11, PSMA-617, HTK01166, and HTK01167 were obtained in 46-69% average decay-corrected radiochemical yield with >99% radiochemical purity and 62.9-152 GBq/μmol average specific activity. PET imaging and biodistribution studies were performed in mice bearing PSMA-expressing LNCap prostate cancer xenografts. All tracers enabled clear visualization of tumors in PET images with excellent tumor-to-background contrast. The uptake values (%ID/g) for tumor and kidneys at 1 h postinjection were 8.91 ± 0.86 and 204 ± 70.6 for Ga-PSMA-11, 16.7 ± 2.30 and 29.2 ± 5.14 forGa-PSMA-617, 14.1 ± 4.40 and 147 ± 59.6 for Ga-HTK01166, and 7.79 ± 1.65 and 4.30 ± 1.80 forGa-HTK01167. The tumor-to-kidney ratios for Ga-labeled PSMA-11, PSMA-617, HTK01166, and HTK01167 were 0.05 ± 0.02, 0.63 ± 0.10, 0.10 ± 0.02, and 1.98 ± 0.63, respectively. Compared withGa-PSMA-617, Ga-HTK01166 showed comparable tumor uptake and almost 5-fold higher kidney uptake, whereasGa-HTK01167 exhibited lower tumor and kidney uptake. Compared with Ga-PSMA-11,Ga-HTK01167 had similar tumor uptake and tumor-to-blood contrast ratio (23.8 ± 6.71 vs 20.4 ± 4.98) but higher tumor-to-background contrast ratios for other background organs especially for kidneys. Our data indicate that substitution of 2-Nal in PSMA-617 with other lipophilic amino acid can modulate PSMA binding affinity and their pharmacokinetics in vivo.

Synthesis and Evaluation of 99mTc-Tricabonyl Labeled Isonitrile Conjugates for Prostate-Specific Membrane Antigen (PSMA) Image

“…The low LogD value of [ 99m Tc]Tc-15 compared to [ 99m Tc]Tc-16 suggests that it is more hydrophilic. However, the presence of two phenyl amino acid groups in the spacer did not show much influence on the LogD value compared to other reports, likely because the phenyl amino groups are hindered inside the trivalent complex [4,54].…”

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

“…Previous studies have demonstrated that there is PSMA expression in normal kidney proximal tubular epithelial cells . Hence, radiation toxicity to kidneys due to the fast clearance of radioligands through the urinary tract is of concern for their application for RLT . However, neither acute nor long‐term kidney toxicity has recently been reported to be a clinical problem in patients treated with [ 177 Lu]Lu‐PSMA‐617 .…”

“…50 Hence, radiation toxicity to kidneys due to the fast clearance of radioligands through the urinary tract is of concern for their application for RLT. 6,51 However, neither acute nor long-term kidney toxicity has recently been reported to be a clinical problem in patients treated with [ 177 Lu]Lu-PSMA-617. 51 It is noteworthy that human kidneys have lower PSMA expression than mouse kidneys.…”

“…In general, PSMA‐targeting ligands have a PSMA‐binding region (motif), a linker (spacer), and a chelator (moiety for radiolabelling) . The linker region is used to adjust molecular size and polarity to impact the in vivo distribution properties . 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.…”

“…5 The linker region is used to adjust molecular size and polarity to impact the in vivo distribution properties. [5][6][7] The most studied PSMA ligands for therapeutic use, PSMA-617 and PSMA-I&T, have different linkers, while the binding motif (glutamateurea moiety) and the chelating moiety (1,4,7,10tetraazacyclododecane-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.…”