Endocrine Abstracts

PSMA-11 belongs to the substance class of peptidomimetic prostate-specific membrane antigen (PSMA) inhibitors. In general, the class of urea-based PSMA inhibitors was firstly described by Kozikowski et al. in 2001 [1] and one of the first preclinical imaging studies using PSMA radioligands in PSMA-positive tumor xenografts were reported by Pomper et al. in 2005 [2]. PSMA is an optimal target both for imaging and therapy of prostate cancer. The now well established PSMA radioligand Ga-68-PSMA-11 for PET imaging of PSMA-positive prostate cancer was clinically introduced in 2011. The first clinical papers on Ga-68-PSMA-11 PET/CT imaging were published in 2012 and 2013 by Afshar-Oromieh et al. [3]. Ga-68-PSMA-11 was developed by the Heidelberg group at the German Cancer Research Center (DKFZ) Heidelberg. Eder et al. published the synthesis and the preclinical evaluation of Ga-68-PSMA-11 [4] which encouraged the aforementioned clinical introduction in Heidelberg. The complexing agent HBED-CC was conjugated to the pharmacophore Glu-urea-Lys. The resulting conjugate PSMA-HBED-CC (PSMA-11) cannot bind clinically relevant therapeutic radiometals such as Lu-177 or Ac-225. PSMA-11 can thus only be used for diagnostic purposes. However it soon became clear that PSMA inhibitors can also be used for PSMA radioligand therapy (PSMA-RLT) of prostate cancer. The first published clinical theranostic approach using radioiodinated versions of the PSMA inhibitor MIP-1095 was reported in 2014 [5]. MIP-1095 was in fact firstly described by Babich et al. in 2009 [6]. As a consequence the Heidelberg group started an initiative to transform the diagnostic tracer PSMA-11 into the theranostic variant PSMA-617 which can also be radiolabelled with the therapeutically relevant trivalent radiometals Lu-177 for beta therapy and Ac-225 for alpha therapy [7], [8]. Consequently, the here intended presentation will describe the chemical transformation of Ga-68-PSMA-11 into Lu-177-PSMA-617 which is currently one of the main candidates for endoradiotherapy (PSMA-RLT) of prostate cancer.

References

1. Kozikowski AP, Nan F, Conti P, et al. J Med Chem. 2001;44(3):298-301.

2. Foss CA, Mease RC, Fan H, et al. Clin Cancer Res 2005;11(11):4022-4028.

3. a. Afshar-Oromieh A, Malcher A, Eder M, et al. Eur J Nucl Med Mol Imaging. 2013 Apr;40(4):486-95. Erratum in: Eur J Nucl Med Mol Imaging. 2013 May;40(5):797-8; b. Afshar-Oromieh A, Haberkorn U, Eder M, et al. Eur J Nucl Med Mol Imaging. 2012 Jun;39(6):1085-6.

4. Eder M, Schäfer M, Bauder-Wüst U, et al. Bioconjugate Chem. 2012 Apr 18;23(4):688-97.

5. Zechmann CM, Afshar-Oromieh A, Armor T, et al. Eur J Nucl Med Mol Imaging. 2014 Jul;41(7):1280-92.

6. Hillier SM, Maresca KP, Femia FJ, et al. Cancer Res. 2009 Sep 1;69(17):6932-40.

7. Benešová M, Bauder-Wüst U, Schäfer M, et al. J Med Chem. 2016 Mar 10;59(5):1761-75.

8. Benešová M, Schäfer M, Bauder-Wüst U, et al. J Nucl Med. 2015 Jun;56(6):914-20.