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Preclinical Evaluation of a Companion Diagnostic Radiopharmaceutical, [18F]PSMA-1007, in a Subcutaneous Prostate Cancer Xenograft Mouse Model


Su Bin Kimet al, Molecular Pharmaceutics, 2022


Several radiolabeled PSMA-targeted agents have been developed for detecting prostate cancer, using positron emission tomography imaging and targeted radionuclide therapy. Among them, [18F]PSMA-1007 has several advantages, including a comparatively long half-life, delayed renal excretion, and compatible structure with α-/β-particle emitter-labeled therapeutics. This study aimed to characterize the preclinical pharmacokinetics and internal radiation dosimetry of [18F]PSMA-1007, as well as its repeatability and specificity for target binding using prostate tumor-bearing mice. In PSMA positive tumor-bearing mice, the kidney showed the greatest accumulation of [18F]PSMA-1007. The distribution in the tumor attained its peak concentration of 2.8%ID/g at 112 min after intravenous injection. The absorbed doses in the tumor and salivary glands were 0.079 ± 0.010 Gy/MBq and 0.036 ± 0.006 Gy/MBq, respectively. The variance of the net influx (Ki) of [18F]PSMA-1007 to the tumor was minimal between scans performed in the same animals (within-subject coefficient of variation = 7.57%). [18F]PSMA-1007 uptake in the tumor was specifically decreased by 32% in Ki after treatment with a PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In the present study, the in vivo preclinical characteristics of [18F]PSMA-1007 were investigated. These data from [18F]PSMA-1007 PET/CT studies in a subcutaneous prostate cancer xenograft mouse model supports clinical therapeutic strategies that use paired therapeutic radiopharmaceuticals (such as [177Lu]LuPSMA-617), especially strategies with a quantitative radiation dose estimate for target lesions while minimizing radiation-induced toxicity to off-target tissues.

Results from nanoScan® PET/CT

PSMA-positive human prostate carcinoma (LNCaP, Lymph node carcinoma of the prostate) cells (1.0 × 107 cells in 200 μL phosphate-buffered saline) were inoculated subcutaneously into the right flank of male BALB/c mice. The tumor sizes measured with calipers after inoculation and before imaging
were 0.689 ± 0.119 cm3.

In the biodistribution and internal radiation dosimetry studies, whole-body PET/CT images were acquired of the eight LNCaP tumor-bearing mice at 0-120 min (dynamic) post-injection of [18F]PSMA-1007. The additional PET/CT scans were repeated 2 days after the first scan (Scan 1) using the same animals to add the second dataset (Scan 2) of PET/CT images for the repeatability analysis.

The other five LNCaP tumor-bearing mice who were assigned to the inhibition group in the specificity study underwent 120 min dynamic whole-body PET/CT scans after treatment with the PSMA-selective inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA).

Results show:

  • [18F]PSMA-1007 demonstrated rapid whole-body distribution immediately after the injection, followed by rapid washout (at variable rates) from peripheral organs, wherease accumulating uptake in the tumor. kidneys showed the highest accumulation of
    [18F]PSMA-1007 without exhibiting a washout phase during the study. The tumor exhibited a peak [18F]PSMA-1007 concentration of 2.86 ± 0.24%ID/g at 112 min (on average)
    after the injection.

Figure 1. Serial PET/CT images of a subcutaneous prostate cancer xenograft mouse model after injection with [18F]PSMA-1007. PET/CT, positron emission tomography/computed tomography; %ID/g, percent injected dose per gram of tissue; H, heart; K, kidney; L, liver; SG, salivary glands; T, prostate-specific membrane antigen-positive tumor (LNCaP); UB, urinary bladder.

Figure 2. Percentage of injected dose per gram (%ID/g) of [18F]PSMA-1007 over time.

  • dosimetry analysis showed kidneys showed the highest absorbed dose

Absorbed Dose Received by Organs of the Subcutaneous Prostate Cancer Xenograft Model Mice after [18F]PSMA-1007 Administration

  • The mean TAC of [18F]PSMA-1007 (SUV) in the tumor of the same animal overlapped completely between scans performed over two consecutive days.
  • Differences in SUV between the baseline and inhibition groups induced by 2-PMPA treatment (50 mg/kg) demonstrated the specific binding of [18F]PSMA-1007 in the PSMA-positive tumor (LNCaP).

Estimated Kinetic Parameters (K1-k3) and the Net Influx Rate Constant (Ki) of [18F]PSMA-1007 for the Irreversible Two-Tissue Compartment Model in the Repeatability and Specificity Studies

Full article on pubs.acs.org

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