mp9b01179_si_001.pdf (158.59 kB)
Development of 18F‑Fluoroglycosylated PSMA-Ligands with Improved Renal Clearance Behavior
journal contribution
posted on 2020-02-14, 22:29 authored by Roman Potemkin, Brigitte Strauch, Torsten Kuwert, Olaf Prante, Simone MaschauerThe
prostate-specific membrane antigen (PSMA) is a type II transmembrane
glycoprotein that is highly expressed in the malignant human prostate
epithelium. Therefore, PSMA has emerged as a very attractive target
for developing radiopharmaceuticals for the diagnosis, e.g., by positron
emission tomography (PET) imaging, and radiotherapy of prostate cancer.
The aim of this study was to develop 18F-labeled PSMA ligands
bearing different 18F-glycosyl moieties to study the effect
on the in vivo clearance behavior of radiotracers
in addition to their tumor binding ability. Therefore, we applied
click chemistry-based 18F-fluoroglcosylation using 2-deoxy-2-[18F]fluoroglucosyl azide or 6-deoxy-6-[18F]fluoroglucosyl
azide as prosthetic groups for the radiosynthesis of the 18F-fluoroglycosylated glutamate-urea-lysine-based PSMA inhibitors
2-[18F]FGlc-PSMA ([18F]7) and 6-[18F]FGlc-PSMA ([18F]8). The PSMA inhibitory
potencies were determined by competitive radioligand binding assays
using 99mTc-MIP-1404 and PSMA-expressing PC-3 PIP cells,
revealing moderate PSMA inhibitory potencies for [18F]7 (IC50 = 234 nM) and [18F]8 (IC50 = 59 nM). Biodistribution and small-animal PET
studies were performed using PSMA-positive PC-3 PIP and PSMA-negative
PC-3 tumor-bearing nude mice. PSMA inhibitors [18F]7 and [18F]8 were obtained in high
radioactivity yields of 19–22% (nondecay-corrected, referred
to [18F]fluoride) and with molar activities of 71–136
GBq/μmol. In the biodistribution studies, the uptake levels
of [18F]7 and [18F]8 in PC-3 PIP tumors were 13 ± 3%ID/g and 6 ± 5%ID/g at
60 min p.i., respectively. PSMA-negative PC-3 tumors and all other
tissues had negligible low uptake values. Interestingly, [18F]7 had high uptake in the kidneys, with remarkable
retention from 30 to 60 min p.i. (74 to 72%ID/g). In contrast, [18F]8 revealed a low uptake of 7.5%ID/g in the
kidneys at 30 min p.i. and was rapidly cleared through the kidney
(0.9%ID/g at 120 min p.i.). In direct comparison to a 68Ga-PSMA-11 PET scan of the same mouse, [18F]7 and [18F]8 showed 2- to 3-fold higher uptake
values in PC-3 PIP tumors. Both radiotracers were solely cleared via
the kidneys and not via the hepatobiliary pathway. The regional kidney
distribution pattern of the tracers in the kidneys revealed that 68Ga-PSMA-11 and 2-[18F]FGlc-PSMA([18F]7) mainly accumulated in the cortex of the kidneys,
whereas 6-[18F]FGlc-PSMA([18F]8) showed a 10-fold lower kidney uptake with accumulation in the inner
medulla or pelvis of the kidneys. Overall, the developed 6-fluoroglucosyl
derivative [18F]8, with its considerably low
kidney uptake and fast clearance, demonstrated high uptake in PSMA-positive
tumors in vivo. This candidate could, therefore,
be valuable for translation into the clinic.
History
Usage metrics
Categories
Keywords
kidney distribution patternPSMA-expressing PC -3 PIP cells18 F-glycosyl moietiespositron emission tomography99 m Tc-MIP -140468 Ga-PSMA -11 PET scanPSMA-negative PC -3 tumor-bearinguptake valuesPC -3 PIP tumorsIDRenal Clearance Behavior68 Ga-PSMA -11kidney uptaketumor binding ability30 min p.itype II transmembrane glycoproteinIC 50vivo clearance behavior60 min p.iclick chemistry-based 18 F-fluoroglcosylationPSMA-positive PC -3 PIPsmall-animal PET studiesradioligand binding assays18 F-labeled PSMA ligandsprostate-specific membrane antigen18 FPSMA-negative PC -3 tumors
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC