Translational assessment of a DATA-functionalized FAP inhibitor with facile 68Ga-labeling at room temperature.

PURPOSE The present study aims at evaluating the preclinical and the clinical performance of [68Ga]Ga-DATA5m.SA.FAPi, which has the advantage to be labeled with gallium-68 at room temperature. METHODS [68Ga]Ga-DATA5m.SA.FAPi was assessed in vitro on FAP-expressing stromal cells, followed by biodistribution and in vivo imaging on prostate and glioblastoma xenografts. Moreover, the clinical assessment of [68Ga]Ga-DATA5m.SA.FAPi was conducted on six patients with prostate cancer, aiming on investigating, biodistribution, biokinetics, and determining tumor uptake. RESULTS [68Ga]Ga-DATA5m.SA.FAPi is quantitatively prepared in an instant kit-type version at room temperature. It demonstrated high stability in human serum, affinity for FAP in the low nanomolar range, and high internalization rate when associated with CAFs. Biodistribution and PET studies in prostate and glioblastoma xenografts revealed high and specific tumor uptake. Elimination of the radiotracer mainly occurred through the urinary tract. The clinical data are in accordance with the preclinical data concerning the organ receiving the highest absorbed dose (urinary bladder wall, heart wall, spleen, and kidneys). Different to the small-animal data, uptake of [68Ga]Ga-DATA5m.SA.FAPi in tumor lesions is rapid and stable and tumor-to-organ and tumor-to-blood uptake ratios are high. CONCLUSION The radiochemical, preclinical, and clinical data obtained in this study strongly support further development of [68Ga]Ga-DATA5m.SA.FAPi as a diagnostic tool for FAP imaging

Streamlined Schemes for Dosimetry of 177Lu-Labeled PSMA Targeting Radioligands in Therapy of Prostate Cancer

(Background) Aim of this retrospective analysis was to investigate in mCRPC patients treated with [177Lu]Lu-PSMA-617 whether the absorbed dose (AD) in organs at risk (OAR, i.e., kidneys and parotid glands) can be calculated using simplified methodologies with sufficient accuracy. For this calculation, results and kinetics of the first therapy cycle were used. (Methods) 46 patients treated with 2 to 6 cycles of [177Lu]Lu-PSMA-617 were included. As reference (current clinical standard) full dosimetry of the OAR based on quantitative imaging (whole body scintigraphy and quantitative SPECT/CT at 2, 24, 48 and 72 h p.i.) for every cycle was used. Alternatively, two dosimetry schemes, simplified in terms of image acquisition and dose calculation, were established, both assuming nearly unchanged kinetics of the radiopharmaceutical for subsequent cycles. (Results) In general, for both OAR the simplified methods provided results that were consistent with the dosimetric reference method, both per cycle and in terms of cumulative AD. Best results were obtained when imaging was performed at 48 h p.i. in each of the subsequent cycles. However, both simplified methods tended to underestimate the cumulative AD. (Conclusion) Simplified dosimetry schemes are feasible to tailor multi-cycle [177Lu]Lu-PSMA-targeted therapies

Representative transverse slices of T2w-MRI, DWI and FDG-PET of the subcutaneously implanted A673 rhabdomyosarcoma xenografts (arrows) pre and 2 days after therapy onset (p.i.) with injection of PRS-050-PEG40, Avastin or PBS as control group.

<p>On T2-weighted MR images the treated tumors showed discreet central hypointense changes indicating apoptosis while the control group did not show significant signal alterations of the tumor tissue. DWI (b = 200) of the PRS-050-PEG40 and Avastin treated tumors shows a small increase in signal intensity while the control group shows a discreet decrease in concordance with the ADC value. FDG-PET demonstrates a decrease in FDG uptake (radioactivity is shown in color scale (Bq/mL)) in the PRS-050-PEG40 and Avastin treated tumor tissue, while the control tumor shows an increase in FDG uptake. Of note, the PET images reveal physiologic cardiac FDG uptake (arrowheads).</p

Semiquantitative analysis of the microvessel density (MVD) as assessed by CD31 and SMA staining.

<p>Quantification (%) of the necrotic areas in the tumor tissue before and 2 or 7 days post therapy (p.t.).</p

Representative H&E, SMA and CD31 stains of PRS-050-PEG40, Avastin or PBS treated tumors at day 2 after onset of therapy.

<p>The representative Anticalin treated tumor shows extensive necrosis (black star) and necroptosis (white star), the Avastin treated tumors shows extensive necrosis and a mitosis (block dot). In contrary the PBS treated control tumor shows no necrosis or apoptosis. The black arrows indicate vessels, black arrowheads indicate musculature and black dash indicates apoptosis.</p

Percentage change of the tumor size.

<p>On day 3 (day 2 after therapy onset) tumor volume between the different groups did not reach a statistical significance (PRS-050-PEG40/Avastin/PBS, P = 0.09). On day 8 (day 7 after therapy onset) tumors in the control group were significantly larger compared to the treatment groups (PRS-050-PEG40/Avastin in comparison to PBS, each P = 0.001). There was no significant difference in the tumor growth between the therapy groups PRS-050-PEG40 and Avastin neither on day 2 nor day 7 after therapy onset (P = 0.13/0.30). Data are mean values.</p

Representative DWI (transverse slices; b = 20, b = 200, ADC map), T1 map (T1 values are shown in color scale (ms)) of DCE-MRI from a single time point (transverse slices; pre and post i.v. injection of Gadolinium) used for T1 quantification and FDG-PET (from left to right: transverse, coronal and sagittal reconstruction) images of the A673 rhabdomyosarcoma xenografts (arrows) subcutaneously implanted in the right lateral flank.

<p>Representative DWI (transverse slices; b = 20, b = 200, ADC map), T1 map (T1 values are shown in color scale (ms)) of DCE-MRI from a single time point (transverse slices; pre and post i.v. injection of Gadolinium) used for T1 quantification and FDG-PET (from left to right: transverse, coronal and sagittal reconstruction) images of the A673 rhabdomyosarcoma xenografts (arrows) subcutaneously implanted in the right lateral flank.</p

Scatter plots illustrating the degree of correlation between the percentage change of tumor size (pre vs. day 7 after onset of therapy) plotted along the horizontal axis versus DWI (hollow circle, r = −0.58, P = 0.001), DCE-MRI (grey circle, r = 0.71, P = 0.001) and FDG-PET (black circle, r = 0.67, P<0.001) (pre vs. day 2 after onset of therapy) plotted along the vertical axis.

<p>Scatter plots illustrating the degree of correlation between the percentage change of tumor size (pre vs. day 7 after onset of therapy) plotted along the horizontal axis versus DWI (hollow circle, r = −0.58, P = 0.001), DCE-MRI (grey circle, r = 0.71, P = 0.001) and FDG-PET (black circle, r = 0.67, P<0.001) (pre vs. day 2 after onset of therapy) plotted along the vertical axis.</p

Percentage change (1.0 = 100%) of all subjects (mean and standard deviation depicted as horizontal and vertical line) of the tumor size, DWI, DCE-MRI and FDG-PET on day 2 after onset of therapy (PRS-050-PEG40 or Avastin) or injection of PBS as control group.

<p>Percentage change (1.0 = 100%) of all subjects (mean and standard deviation depicted as horizontal and vertical line) of the tumor size, DWI, DCE-MRI and FDG-PET on day 2 after onset of therapy (PRS-050-PEG40 or Avastin) or injection of PBS as control group.</p