2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer

Abstract

Purpose: We have synthesized and evaluated in vivo 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [(18)F]DCFPyL, as a potential imaging agent for the prostate-specific membrane antigen (PSMA). PSMA is upregulated in prostate cancer epithelia and in the neovasculature of most solid tumors.

Experimental design: [(18)F]DCFPyL was synthesized in two steps from the p-methoxybenzyl (PMB) protected lys-C(O)-glu urea precursor using 6-[(18)F]fluoronicotinic acid tetrafluorophenyl ester ([(18)F]F-Py-TFP) for introduction of (18)F. Radiochemical synthesis was followed by biodistribution and imaging with PET in immunocompromised mice using isogenic PSMA PC3 PIP and PSMA- PC3 flu xenograft models. Human radiation dosimetry estimates were calculated using OLINDA/EXM 1.0.

Results: DCFPyL displays a K(i) value of 1.1 ± 0.1 nmol/L for PSMA. [(18)F]DCFPyL was produced in radiochemical yields of 36%-53% (decay corrected) and specific radioactivities of 340-480 Ci/mmol (12.6-17.8 GBq/μmol, n = 3). In an immunocompromised mouse model [(18)F]DCFPyL clearly delineated PSMA+ PC3 PIP prostate tumor xenografts on imaging with PET. At 2 hours postinjection, 39.4 ± 5.4 percent injected dose per gram of tissue (%ID/g) was evident within the PSMA+ PC3 PIP tumor, with a ratio of 358:1 of uptake within PSMA+ PC3 PIP to PSMA- PC3 flu tumor placed in the opposite flank. At or after 1 hour postinjection, minimal nontarget tissue uptake of [(18)F]DCFPyL was observed. The bladder wall is the dose-limiting organ.

Conclusions: These data suggest [(18)F]DCFPyL as a viable, new positron-emitting imaging agent for PSMA-expressing tissues.

©2011 AACR.

Figures

Figure 1

Synthesis of [18F]DCFPyL [18F]3 and DCFPyL 3. a) 6-Fluoro-nicotinic acid-2,3,5,6-tetrafluoro-phenyl ester, Et3N, CH2Cl2; b) TFA/CH2Cl2; c) 6-[18F]fluoro-nicotinic acid-2,3,5,6-tetrafluoro-phenyl ester; d) TFA/anisole.

Figure 2

PET-CT volume-rendered composite images representing the time course of radiochemical uptake after administration of [18F]DCFPyL ([18F]3). PSMA+ PC3 PIP (arrow) and PSMA− PC3 flu (dotted oval) tumors are present in subcutaneous tissues posterior to opposite forearms, as indicated. The mouse was injected intravenously with 0.38 mCi (14.1 MBq) [18F]DCFPyL ([18F]3) at Time 0. By 30 min post-injection radiochemical uptake was evident within the PIP tumor and kidneys. Radioactivity receded from kidneys faster than from tumor, and was not evident within kidneys by 3.5 h post-injection. Radioactivity within bladder was due to excretion. At no time was radiochemical clearly visualized within the flu tumor. kid = kidneys, bl = urinary bladder.