Preclinical Evaluation of a Fibroblast Activation Protein and a Prostate-Specific Membrane Antigen Dual-Targeted Probe for Noninvasive Prostate Cancer Imaging

Abstract

Prostate-specific membrane antigen (PSMA) is a prostate cancer target that plays a crucial role in prostate cancer diagnosis and therapy. Herein, a novel dual-targeted imaging probe, [68Ga]Ga-FAPI-PSMA, was prepared by radiolabeling conjugated DOTA-FAPI-PSMA with the short half-life radionuclide gallium-68 (68Ga), which is dedicated to prostate cancer diagnostic imaging. In vitro, [68Ga]Ga-FAPI-PSMA had higher affinity for the PSMA and FAP high-expressing cell lines 22Rv1 and U87 MG with IC50 values of 4.73 and 2.10 nM, respectively, than in the corresponding negative expression cell lines PC3 and A549, and significant differences in cell uptake were also observed. In vivo, [68Ga]Ga-FAPI-PSMA was rapidly cleared from the body, and the estimated radiation dose was relatively low compared with several other FAPI probes. In 22Rv1 and U87 MG tumor xenografts, [68Ga]Ga-FAPI-PSMA rapidly accumulated in tumors after administration, and the best images can be obtained at 1 h postinjection. In conclusion, the dual-targeted probe [68Ga]Ga-FAPI-PSMA was successfully prepared for in vivo prostate cancer PET/CT imaging.

Advances in macrocyclic chelators for positron emission tomography imaging

“…68 Ga 3+ is a typical hard (radio)metal (I A = 7.07) that prefers oxygen and nitrogen ligands for the formation of stable complexes. 10 Fast and stable 68 Ga radiolabeling can be achieved by the classic macrocycle chelators such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and NOTA (N,N′,N″-(1,4,7-triazacyclononane-1,4,7triyl)triacetic acid; Figure 2). 12 DOTA is a cyclen-based chelator, the most often used macrocyclic chelator for PET applications.…”

“…12 DOTA is a cyclen-based chelator, the most often used macrocyclic chelator for PET applications. DOTA macrocycle is the basis for two of the four 68 Ga radiopharmaceuticals approved by the FDA. 28 Compared with smaller macrocyclic chelating agents, large-sized macrocycles are less suitable for Ga 3+ complexation (log K Ga-DOTA = 26.05).…”

“…28 Compared with smaller macrocyclic chelating agents, large-sized macrocycles are less suitable for Ga 3+ complexation (log K Ga-DOTA = 26.05). 29,30 Therefor, work has been done to develop DOTA-based BFCs as well as cyclen-based and other azamacrocyclic 68 Ga chelators for radiopharmaceutical applications. 31 Tunable 68 Ga-labeled DO3A and DO2A-like macrocycles were studied by Smith et al for myocardial perfusion imaging.…”

“…32,33 Typically, myocardial perfusion imaging is performed using lipophilic cations. [34][35][36] A series of DO3A chelators for 68 Ga chelation, functionalized with triarylphosphonium (TAP) moiety including triphenylphosphonium (TPP), tritolylphosphonium (TTP), and trixylylphosphonium (TXP) were tested. The most lipophilic tracers of this series, [ 68 Ga]Ga-DO3A-xy-TXP exhibited less than 1% retention in ex vivo isolated perfused rat hearts, a result of its low lipophilicity (logD 7.4 , −1.81 ± 0.02) in comparison to "gold standard" [ 99m Tc]Tc-SestaMIBI (logD 7.4 , 1.29, and approximately 40% uptake in healthy hearts).…”

“…[34][35][36] A series of DO3A chelators for 68 Ga chelation, functionalized with triarylphosphonium (TAP) moiety including triphenylphosphonium (TPP), tritolylphosphonium (TTP), and trixylylphosphonium (TXP) were tested. The most lipophilic tracers of this series, [ 68 Ga]Ga-DO3A-xy-TXP exhibited less than 1% retention in ex vivo isolated perfused rat hearts, a result of its low lipophilicity (logD 7.4 , −1.81 ± 0.02) in comparison to "gold standard" [ 99m Tc]Tc-SestaMIBI (logD 7.4 , 1.29, and approximately 40% uptake in healthy hearts). The compounds with higher lipophilicity 68 Ga-DO2A-(xy-TXP) 2 (logD 7.4 , −0.28 ± 0.01) and 68 Ga-DO2A-xy 2 (logD 7.4 , 0.31 ± 0.01) based on DO2A and furnished with two TAP or aromatic pendant arms.…”