Metal-Based PSMA Radioligands

Abstract

Prostate cancer is one of the most common malignancies for which great progress has been made in identifying appropriate molecular targets that would enable efficient in vivo targeting for imaging and therapy. The type II integral membrane protein, prostate specific membrane antigen (PSMA) is overexpressed on prostate cancer cells in proportion to the stage and grade of the tumor progression, especially in androgen-independent, advanced and metastatic disease, rendering it a promising diagnostic and/or therapeutic target. From the perspective of nuclear medicine, PSMA-based radioligands may significantly impact the management of patients who suffer from prostate cancer. For that purpose, chelating-based PSMA-specific ligands have been labeled with various diagnostic and/or therapeutic radiometals for single-photon-emission tomography (SPECT), positron-emission-tomography (PET), radionuclide targeted therapy as well as intraoperative applications. This review focuses on the development and further applications of metal-based PSMA radioligands.

Keywords: PET; SPECT; intraoperative applications.; prostate specific membrane antigen (PSMA); radionuclide therapy.

Figure 1

The enzyme actions of PSMA. (a) Glutamic acid is released from folate polyglutamate; (b) N-Acetyl-l-aspartyl-l-glutamate (NAAG) is hydrolyzed to aspartate (NAA) and glutamate (l-Glu).

Figure 2

PSMA inhibitors. 2-PMPA (1) is the first potent PSMA inhibitor. The three groups of PSMA inhibitors include: thiols 2 and 3, phosphonates 4 and ureas 5 and 6.

Figure 3

Chemical structures of the ^99mTc-labeled GPI (7) GPI monomer (8), GPI dimer (9) and GPI trimer (10) [72,73].

Figure 4

Chemical structure of ^99mTc(CO)₃-DTPA-CTT-54 (11) [74].

Figure 5

Chemical structure of ⁶⁴Cu-ABN-1 (12) [75].

Figure 6

PSMA-inhibitors labeled via the ([^99mTcO]³⁺) (13–20), ([^99mTc(CO)₃]⁺) (21–24) and (^99mTc-hynic) (25) core [98,99].

Figure 7

^99mTc-labeled PSMA inhibitors (26–31) [100].

Figure 8

Chemical structure of ^99mTc-MAS₃ (32)/mas₃ (33)-y-nal-k-Sub-KuE (MAS₃/mas₃-D-Tyr-D-2-Nal-D-Lys-suberoyl-Lys-urea-Glu) [101].

Figure 9

Chemical structure of ^99mTc-TMCE (34) [102].

Figure 10

Chemical structures of ^99mTc-MIP-1428 (35), ^99mTc-MIP-1405 (36), ^99mTc-MIP-1404 (37) and ^99mTc-MIP-1427 (38) [103].

Figure 11

Chemical structures of the monomer ⁶⁸Ga-PSMA-11 (39) and the dimer ⁶⁸Ga-PSMA-10 (40) [106,130].

Figure 12

Chemical structures of the two DOTA- (41 and 42) and the NOTA-conjugated (43) PSMA inhibitors labeled with ⁶⁸Ga [131,132].

Figure 13

Chemical structure of ⁶⁸Ga-PSMA-617 (44) [133].

Figure 14

Chemical structures of the three generations (DOTAGA-FFK(Sub-KuE) (45), DOTAGA-ffk(Sub-KuE) (46) and of DOTAGA-(I-y)fk(Sub-KuE) (47)) PSMA inhibitors labeled with ⁶⁸Ga [134,135].

Figure 15

Chemical structure of ⁶⁸Ga-(R)-NODAGA-Phe-Phe-d-Lys(suberoyl)-Lys-urea-Glu (⁶⁸Ga-CC34) (48) [136].

Figure 16

Chemical structure of ⁶⁸Ga-CHX-A″-DTPA-DUPA-Pep (49) [137].

Figure 17

Chemical structures of the PSMA-based inhibitors (50–54) labeled with ⁶⁴Cu [139].

Figure 18

Tumor uptake of ^99mTc-MIP-1404 (A) or ^99mTc-MIP-1405 (B) at 4 h in patient with metastatic prostate cancer, compared with that of standard bone scan (C). Images also show uptake of radiotracer in normal parotid and salivary glands. Ant = anterior; Post = posterior (Reprinted with permission of [143]).

Figure 19

⁶⁸Ga-PSMA-11 PET/CT image of a patient with locally recurrent prostate cancer (PSA 3.7 ng/mL) after radical prostatectomy (SUVmax 12.4) who received 140 MBq of the ⁶⁸Ga-labeled tracer molecule and was scanned at 1 h p.i.; (a) CT image; (b) PET image; (c) PET/CT fusion image; (d) MIP (Reprinted with permission of [145]).

Figure 20

(A–C) ⁶⁸Ga-PSMA-617 PET/CT of a patient at 1 h after injection. Red arrows point to a bone metastasis with SUVmax of 21.7 at 1 h and 32.6 at 3 h after injection. (A) Low dose CT; (B) Fusion of PET and CT; (C) MIP of PET/CT. MIP = maximum-intensity projection (Reprinted with permission of [146]).

Figure 21

70-year-old patient with PSMA-avid lymph node metastases on ⁶⁸Ga-PSMA PET/CT before therapy (A) and on ¹⁷⁷Lu-PSMA I&T scintigraphy after first PSMA radionuclide therapy (B); with remarkable reduction in uptake after second PSMA RLT (C). Results were consistent with excellent therapy response projection (Reprinted with permission of [153]).