Molecular Imaging of Prostate Cancer: A direct comparison of the preclinical characteristics of [¹⁸F]DCFPyL and [¹⁸F]PSMA-1007 and the impact of glutamic acids on [¹⁸F]PSMA-1007

Aim: For the imaging of PSMA-positive prostate cancer, several fluorine-18 (¹⁸F)-labelled compounds have been developed and translated into the clinics. Next to a clinical study comparing the tracer-specific characteristics of [¹⁸F]DCFPyL and [¹⁸F]PSMA-1007 intra-individually(1), a direct comparison of their preclinical characteristics has only recently been published(2). In this work, the importance of glutamic acids in the structure of [¹⁸F]PSMA-1007 is further elucidated using derivatives with none to three glutamic acids (Glu), respectively. Furthermore, [¹⁸F]DCFPyL and [¹⁸F]PSMA-1007 are evaluated regarding their preclinical characteristics using the in vitro and in vivo methods established at DKFZ Heidelberg, Germany. Materials and Methods: The precursors for radiofluorination containing different amino acid linkers (0-3 Glu) were synthesized by means of solid phase chemistry. The radiolabeling of [¹⁸F]PSMA-1007, its derivatives, and [¹⁸F]DCFPyL were performed prior to each experiment as described(3,4). The binding affinities of non-radioactive reference compounds were determined by competitive binding assays against [⁶⁸Ga]Ga-PSMA-10 in LNCaP cells. The internalization of the respective radioligands in LNCaP cells was compared. Biodistribution and pharmacokinetics were evaluated in vivo in LNCaP-tumor bearing BALB/c Nude mice using μPET. Results: The Glu variation in the linker structure resulted in similar binding affinities (Ki 3-14 nM) whereby the insertion of three Glu showed the highest Ki values. Internalization assays revealed that the insertion of Glu influences the internalization rate, whereby the insertion of two Glu ([¹⁸F]PSMA-1007) leads to the highest internalization rate (54.04±13.7%) in a total range between 27.3±3% to 54±13.7%. In comparison to [¹⁸F]PSMA-1007, a higher proportion of [¹⁸F]DCFPyL remains cell surface bound; only 27.83 ± 4.31% of the radiotracer is internalized. [¹⁸F]DCFPyL also has a slightly lower binding affinity (18.02±9.63 nM). μPET imaging showed outstanding imaging properties, especially of [¹⁸F]DCFPyL and [¹⁸F]PSMA-1007. In mice, the liver uptake is reduced by introduction of Glu linkers. The data will be analysed more detailed soon. Conclusion: Comparative cell experiments revealed a high binding affinity for all tracers and the highest internalization rate for [¹⁸F]PSMA-1007. The insertion of Glu in the linker structure plays an important role in pharmacokinetics due to the decreased lipophilicity of the respective radiotracer. Especially [¹⁸F]DCFPyL and [¹⁸F]PSMA-1007 are of excellent imaging quality. Their apparent non-inferiority is currently under further assessment in clinical trials. References: (1) Giesel F et al (2017): JNM, doi: 10.2967/jnumed.117.204669. (2) Robu S et al (2018): EJNMMI Res., 8(1):30. (3) Cardinale J et al. (2017): JNM, 58(3):425-431. (4) Chen Y et al. (2011): Clin Cancer Res., 17(24):7645-53.