Radiohybrid Ligands: A Novel Tracer Concept Exemplified by ¹⁸F- or ⁶⁸Ga-Labeled rhPSMA Inhibitors

Abstract

When we critically assess the reason for the current dominance of 68 Ga-labeled peptides and peptide-like ligands in radiopharmacy and nuclear medicine, we have to conclude that the major advantage of such radiopharmaceuticals is the apparent lack of suitable 18 F-labeling technologies with proven clinical relevance. To prepare and to subsequently perform a clinical proof-of-concept study on the general suitability of silicon-fluoride-acceptor (SiFA)-conjugated radiopharmaceuticals, we developed inhibitors of the prostate-specific membrane antigen (PSMA) that are labeled by isotopic exchange (IE). To compensate for the pronounced lipophilicity of the SiFA unit, we used metal chelates, conjugated in close proximity to SiFA. Six different radiohybrid PSMA ligands (rhPSMA ligands) were evaluated and compared with the commonly used 18 F-PSMA inhibitors 18 F-DCFPyL and 18 F-PSMA-1007. Methods: All inhibitors were synthesized by solid-phase peptide synthesis. Human serum albumin binding was measured by affinity high-performance liquid chromatography, whereas the lipophilicity of each tracer was determined by the n-octanol/buffer method. In vitro studies (IC 50 , internalization) were performed on LNCaP cells. Biodistribution studies were conducted on LNCaP tumor-bearing male CB-17 SCID mice. Results: On the laboratory scale (starting activities, 0.2-9.0 GBq), labeling of 18 F-rhPSMA-5 to -10 by IE was completed in , 20 min (radiochemical yields, 58% ± 9%; radiochemical purity, .97%) with molar activities of 12-60 GBq/μmol. All rhPSMAs showed low nanomolar affinity and high internalization by PSMA-expressing cells when compared with the reference radiopharmaceuticals, medium-to-low lipophilicity, and high human serum albumin binding. Biodistribution studies in LNCaP tumorbearing mice revealed high tumor uptake, sufficiently fast clearance kinetics from blood, low hepatobiliary excretion, fast renal excretion, and very low uptake of 18 F activity in bone. Conclusion: The novel 18 F-rhPSMA radiopharmaceuticals developed under the radiohybrid concept show equal or better targeting characteristics than the established 18 F-PSMA tracers 18 F-DCFPyL and 18 F-PSMA-1007. The unparalleled simplicity of production, the possibility to produce the identical 68 Ga-labeled 19 F-68 Ga-rhPSMA tracers, and the possibility to extend this concept to true theranostic radiohybrid radiopharmaceuticals, such as F-Lu-rhPSMA, are unique features of these radiopharmaceuticals.

Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics

“…The four isomers ([ 19 F, nat Ga]rhPSMA-7.1-7.4) were prepared via SPPS by means of modifying the recently published protocol for diastereomeric mixture [ 19 F, nat Ga] rhPSMA-7 (see Additional file 1: Figs. 1 to 5) [15].…”

“…Due to the superior nuclear properties of the fluorine-18 radionuclide and accompanying logistic and economic advantages [10,11], a shift of interest from 68 Ga-labeled PSMA tracers toward 18 F-labeled analogues has been observed in recent years [12][13][14]. In this context radiohybrid (rh) PSMA ligands, developed by our group, form a novel class of radiopharmaceuticals, which combine a Silicon-Fluoride-Acceptor (SiFA) and a metal chelate (or a chelator) in a single molecule [15]. Such rhPSMA ligands can either be labeled with fluorine-18 by isotopic exchange at the SiFA-moiety in the presence of a non-radioactive metal chelate (e.g., nat Ga-or nat Luchelate), or with a radiometal (e.g., [ 68 Ga]Gallium, [ 177 Lu] Lutetium, [ 225 Ac]Actinium) by means of the chelator, while the SiFA moiety is non-radioactive [15].…”

“…In this context radiohybrid (rh) PSMA ligands, developed by our group, form a novel class of radiopharmaceuticals, which combine a Silicon-Fluoride-Acceptor (SiFA) and a metal chelate (or a chelator) in a single molecule [15]. Such rhPSMA ligands can either be labeled with fluorine-18 by isotopic exchange at the SiFA-moiety in the presence of a non-radioactive metal chelate (e.g., nat Ga-or nat Luchelate), or with a radiometal (e.g., [ 68 Ga]Gallium, [ 177 Lu] Lutetium, [ 225 Ac]Actinium) by means of the chelator, while the SiFA moiety is non-radioactive [15]. The chemical identity of the 18 7) has already been assessed for PET imaging of primary and metastatic castration-resistant prostate cancer.…”

Insight into the Development of PET Radiopharmaceuticals for Oncology

“…This represents a simple pathway for the development of theranostic pairs for cancer. Moreover, there is the potential to develop dual-labeled radiotheranostics with a chelator for a therapeutic radioisotope and another prosthetic group for a PET radioisotope (e.g., silicon-fluoride or trifluoroborate) [200][201][202].…”

Safety, Biodistribution, and Radiation Dosimetry of 18F-rhPSMA-7.3 in Healthy Adult Volunteers

“…18 F-labeled PSMA agents are increasingly used in preference to 68 Ga-labeled ones because of the favorable characteristics of the 18 F isotope. These include a longer half-life, capability for production of larger batches, a higher positron yield and lower positron energy, which results in decreased image noise and improved contrast resolution compared with 68 Galabeled counterparts (6,7). Many 18 F-labeled PSMA ligands have been used clinically, in particular DCFPyL and PSMA-1007 have been used in large numbers of patients (8).…”