First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer

Abstract

This phase 1 study was performed to determine the pharmacokinetics and ability to visualize prostate cancer in bone, soft-tissue, and the prostate gland using 123 I-MIP-1072 and 123 I-MIP-1095, novel radiolabeled small molecules targeting prostate-specific membrane antigen. Methods: Seven patients with a documented history of prostate cancer by histopathology or radiologic evidence of metastatic disease were intravenously administered 370 MBq (10 mCi) of 123 I-MIP-1072 and 123 I-MIP-1095 2 wk apart in a crossover trial design. 123 I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2-3 d. Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM. Results: 123 I-MIP-1072 and 123 I-MIP-1095 visualized lesions in soft tissue, bone, and the prostate gland within 0.5-1 h after injection, with retention beyond 48 h. Target-to-background ratios from planar images averaged 2:1 at 1 h, 3:1 at 4-24 h, and greater than 10:1 at 4 and 24 h for SPECT/CT. Both agents cleared the blood in a biphasic manner; clearance of 123 I-MIP-1072 was approximately 5 times faster. 123 I-MIP-1072 was excreted in the urine, with 54% and 74% present by 24 and 72 h, respectively. In contrast, only 7% and 20% of 123 I-MIP-1095 had been renally excreted by 24 and 72 h, respectively. Estimated absorbed radiation doses were 0.054 versus 0.110 mGy/MBq for the kidneys and 0.024 versus 0.058 mGy/MBq for the liver, for 123 I-MIP-1072 and 123 I-MIP-1095, respectively. Conclusion: 123 I-MIP-1072 and 123 I-MIP-1095 detect lesions in soft tissue, bone, and the prostate gland at as early as 1-4 h. These novel radiolabeled small molecules have excellent pharmacokinetic and pharmacodynamic profiles and warrant further development as diagnostic and potentially when labeled with 131 I therapeutic radiopharmaceuticals.

Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers

“…This side-by-side comparison should be the next step in clinical settings. Phase 0 comparison studies were performed in the first human trials with PSMA inhibitors, namely, MIP-1072 and MIP-1095 (19), and in the initial clinical evaluation of MIP-1404 and MIP-1405 (36). Interindividual (or even intraindividual) patient examinations helped determine the optimal PSMA radioligand for each intended PC option (imaging or therapy).…”

“…The tracer MIP-1095 was first described by Hillier et al in 2009 (Fig. 3) (5), and the first-in-human evaluation of the 123 I-labeled version was finally published in 2013 (19). As a consequence of those findings, the group in Heidelberg, Germany, started an initiative to transform the diagnostic tracer PSMA-11 into the theranostic variant PSMA-617, which can also be radiolabeled with the therapeutically relevant trivalent radiometals 177 Lu or 90 Y for b-therapy and 225 Ac for a-therapy.…”

The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions

“…During the last 2 decades, many efforts have been undertaken to develop PSMA ligands (8)(9)(10)(11)(12)(13)(14)(15)(16). One of these ligands, the smallmolecule Glu-NH-CO-NH-Lys-(Ahx)-[ 68 Ga(HBED-CC)], also known as PSMA-11, PSMA HBED , Glu-CO-Lys(Ahx)-HBED-CC, DKFZ-PSMA-11, PSMA-HBED-CC, PSMA-HBED, PSMA, or Prostamedix, developed at the German Cancer Research Center Heidelberg (DKFZ), has become the most clinically used radiotracer.…”

PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013

“…The related compounds 123 I-MIP-1072 and 123 I-MIP-1095, also bearing a urea-based scaffold, have been used to detect metastatic prostate cancer with SPECT (19). These small molecules demonstrated a potential for therapy when labeled with 131 I (20).…”