Synthesis of N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L-cysteine, [18F]DCFBC, its biodistribution, and use in imaging prostate cancer xenografts

Abstract

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Objectives: Objectives: Previously, we demonstrated successful PET imaging of Prostate Specific Membrane Antigen (PSMA) expressing xenografts using the PSMA inhibitor N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[11C]methyl-L-cysteine, [11C]DCMC (Clin. Cancer. Res. 11:4022 2005). The goal of this work was to prepare and test an F-18 labeled PSMA inhibitor.

Methods: Methods: The precursor (S)-2-[3-[(R)-1-carboxy-2-mercaptoethyl]ureido]-pentanedioic acid was synthesized by a modification of a previously described procedure ( J. Med. Chem. 44: 298 2001). 4-[18F]fluorobenzyl bromide was prepared as previously reported (J. Label. Comp. and Radiopharm. 47: 469 2004). The radiotracer [18F]DCFBC was prepared by reacting 4-[18F]fluorobenzyl bromide with the precursor in ammonia saturated methanol at 60oC for 10 min. followed by purification using C-18 reverse phase semi-preparative HPLC. The specific activity ranged between 350-3,600 Ci/mmol with an average of 1,392 Ci/mmol (n = 6). SCID mice bearing a PSMA + PC-3 PIP tumor on one shoulder and a PSMA - PC-3 FLU tumor on the other shoulder were injected via tail vein with either 50μCi of [18F]DCFBC for biodistribution or 200μCi of [18F]DCFBC for imaging. Imaging was performed on the GE eXplore Vista small animal PET scanner by collecting twelve consecutive 10 min frames. For biodistribution, mice (four per time point) were sacrificed at 5, 15, 30, 60, and 120 min; the tumor, blood, and major organs were harvested, weighed, and radioactivity counted.

Results: Results: The biodistribution and imaging showed PSMA selective tumor uptake of [18F]DCFBC in PSMA+ PC-3 PIP tumors with little to no uptake in PSMA- PC-3 FLU tumors, High uptake was also seen in kidneys and bladder; however, washout of activity from these organs was faster than from PC-3 PIP tumors. The maximum specific PC-3 PIP tumor uptake of [18F]DCFBC (8.16 ± 2.55 %ID/g) was achieved at 60 min. This decreased to 4.69 ± 0.89 at 120 min. Sixty min. and 120 min. PC-3 PIP tumor(T)/blood, T/liver, T/bone/ and T/muscle ratios were 5.0, 1.6, 4.7, 14.3 and 13.0, 2.2, 2.0, 20 respectively.

Conclusions: Conclusion: [18F]DCFBC localizes to PSMA expressing tumors in mice permitting tumor imaging by small-animal PET. This new tracer is an attractive candidate for further studies of PET imaging of Prostate Cancer.