Abstract
Currently, the use of prostate-specific membrane antigen (PSMA)-targeted radiotracers, e.g., 99mTc-labelled PSMA tracer analogues for radioguided surgery, is revolutionising prostate cancer surgery. The purpose of this study was to develop a second-generation 99mTc-labelled PSMA tracer incorporating a fluorescent dye. Methods: PSMA-targeting hybrid tracers were synthesised: EuK-Cy5-mas3, EuK-(SO3)Cy5-mas3, EuK-Cy5(SO3)-mas3, EuK-(Ar)Cy5-mas3, EuK-Cy5(Ar)-mas3; the Cy5 dye acts as a functional backbone between the EuK targeting vector and the mas3 chelate to study the dye’s interaction with PSMA’s amphipathic entrance funnel. Compounds were evaluated for their photophysical and chemical properties and PSMA affinity. Following radiolabelling with 99mTc, in vivo SPECT imaging, biodistribution and fluorescence imaging was conducted in BALB/c nude mice with orthotopically transplanted PC346C tumours. Results: The dye composition influenced the photophysical properties (0.3–1.5 · 104 M-1 · cm-1), plasma protein interactions (85.0 ± 2.3–90.7 ± 1.3% bound to serum, 76 ± 0–89 ± 6% stability in serum), PSMA affinity (IC50 range 19.2 ± 5.8–175.3 ± 61.1 nM) and in vivo characteristics (tumour-to-prostate and tumour-to-muscle ratio: respectively 0.02 ± 0.00–154.73 ± 28.48 and 0.46 ± 0.28–5157.50 ± 949.17; renal, splenic and salivary retention). Even though all tracer analogues allowed tumour identification with SPECT and fluorescence imaging, 99mTc-EuK-(SO3)Cy5-mas3 portrayed the most promising properties (e.g, IC50 = 19.2 ± 5.8, tumour-to-muscle ratio 5157.50 ± 949.17) of all compounds tested. Conclusion: Our findings demonstrate the intrinsic integration of a fluorophore in the pharmacophore in PSMA-targeting small-molecule tracers. In this design having one sulfonate on the indole moiety adjacent to EuK (99mTc-EuK-(SO3)Cy5-mas3) yielded the most promising tracer candidate for the imaging of PSMA.
- Molecular Imaging
- Oncology: GU
- Optical
- cyanine
- hybrid tracers
- image-guided surgery
- prostate cancer
- prostate-specific membrane antigen
- Copyright © 2019 by the Society of Nuclear Medicine and Molecular Imaging, Inc.