68Ga-PSMA-11 PET/CT derived quantitative volumetric tumor parameters for classification and evaluation of therapeutic response of bone metastases in prostate cancer patients.

BACKGROUND: To evaluate the role of 68Gallium prostate-specific membrane antigen-positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) derived quantitative volumetric tumor parameters in comparison with fully diagnostic conventional CT and serum-PSA levels for classification and evaluation of therapeutic response of bone metastases in patients with metastasized prostate cancer (PC). METHODS: A total of 177 men with biochemical recurrence of prostate cancer suffering from bone metastases underwent PET/CT with [68Ga] Ga-PSMA-HBED-CC (68Ga-PSMA-11). To calculate 68Ga-PSMA-11 PET quantitative volumetric tumor parameters including whole-body total-lesion PSMA (TL-PSMA), whole-body PSMA-tumor volume (PSMA-TV), as well as the established maximum standard uptake values (SUVmax) and mean standard uptake values (SUVmean), all 443 68Ga-PSMA-11-positive bone lesions in the field of view were assessed quantitatively. Quantitative volumetric tumor parameters were correlated with CT-derived volume and bone density measurements of metastatic bone lesions, serum prostate-specific antigen (PSA) levels, and Gleason Scores. In the 20 patients suffering from bone metastases who underwent 68Ga-PSMA-11 PET/CT before and after therapy, CT-derived volume and bone density measurements of metastatic lesions were compared to biochemical response determined by serum-PSA levels. RESULTS: In 177 patients, a total of 443 68Ga-PSMA-11 PET-positive bone lesions were detected. Of these, 50 lesions (11%) were only detectable on PET but not on conventional CT. PET-positive/CT-negative bone metastases demonstrated a significantly lower PSMA uptake compared to PET-positive/CT-positive bone lesions (p < 0.05). SUVmax, SUVmean, PSMA-TV, and TL-PSMA of bone metastases were significantly higher (p < 0.05) in patients with Gleason Scores > 7 compared to those with Gleason Scores ≤ 7. In the linear regression analysis, an association was determined between SUVmean, Gleason Scores, lesion classification, and serum-PSA levels but not for CT-derived bone density measurements. No significant correlation could be found between changes of bone density and CT-derived volume measurements of metastatic bone lesions and changes of serum-PSA levels (p > 0.05) before and after therapy, while a highly significant correlation was observed for changes of PSMA-TV, TL-PSMA, and serum-PSA levels (p < 0.001). CONCLUSION: Our results suggest that 68Ga-PSMA-11 PET/CT might be a valuable tool for the detection and follow-up of bone metastases in patients with metastasized prostate cancer. 68Ga-PSMA-11 PET-derived quantitative volumetric parameters demonstrated a highly significant correlation with changes of serum-PSA levels during the course of therapy. No such correlation could be determined for bone density measurements of metastatic bone lesions. Compared to the fully diagnostic CT scan, a significantly higher proportion of bone metastases was detected on 68Ga-PSMA-11 PET.

68Ga-PSMA-11 PET/CT-derived metabolic parameters for determination of whole-body tumor burden and treatment response in prostate cancer.

PURPOSE: We aimed at evaluating the role of 68Ga-PSMA-11 PET/CT-derived metabolic parameters for assessment of whole-body tumor burden and its capability to determine therapeutic response in patients with prostate cancer. METHODS: A total of 142 patients with biochemical recurrence of prostate cancer underwent PET/CT with [68Ga]Ga-PSMA-HBED-CC (68Ga-PSMA-11). Quantitative assessment of all 641 68Ga-PSMA-11-positive lesions in the field of view was performed to calculate PSMA-derived parameters, including whole-body PSMA tumor volume (PSMA-TV) and whole-body total lesion PSMA (TL-PSMA), as well as the established SUVmax and SUVmean values. All PET-derived parameters were tested for correlation with serum PSA levels and for association with Gleason scores. In 23 patients who underwent 68Ga-PSMA-11 PET/CT before and after therapy with either external beam radiation, androgen deprivation, or docetaxel chemotherapy, SUVmax and TL-PSMA were compared to radiographic response assessment of CT images based on RECIST 1.1 criteria and to biochemical response determined by changes of serum PSA levels. RESULTS: PSMA-TV and TL-PSMA demonstrated a significant correlation with serum PSA levels (P < 0.0001) and TL-PSMA was significantly different for different Gleason scores. The agreement rate between TL-PSMA derived from PET and biochemical response was 87% (95% confidence interval, 0.66-0.97; Cohen's κ = 0.78; P < 0.01) and, thus, higher than for SUVmax, which was 74% (95% CI, 0.52-0.90; κ = 0.55; P < 0.01). Furthermore, agreement with PSA was higher for TL-PSMA and SUVmax than for CT-based response evaluation. Discordant findings between PET and CT were most likely due to limitations of CT and RECIST in rating small lymph nodes as metastases, as well as bone involvement, which was sometimes not detectable in CT. CONCLUSION: 68Ga-PSMA-11 PET/CT-derived metabolic tumor parameters showed promising results for evaluation of treatment response. Especially, TL-PSMA demonstrated higher agreement rates with biochemical response compared to SUVmax. Larger, ideally prospective trials are needed to help to reveal the full potential of metabolic parameters derived from PET imaging with 68Ga-PSMA-11.

Synthesis, radiofluorination, and in vitro evaluation of pyrazolo[1,5-a]pyridine-based dopamine D4 receptor ligands: discovery of an inverse agonist radioligand for PET.

A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5- a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D 4 receptor (D 4R) ligands ( 3a- 3h, K i = 1.3-28 nM). The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D 4 subtype selectivity of more than 3 orders of magnitude over both congeners D 2 and D 3 combined with inverse agonism at D 4R. The corresponding (18)F-labeled radioligands revealed high serum stability in vitro and log P values of 2-3. In vitro rat brain autoradiography showed specific binding of [ (18)F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65-80%) and the selective D 4R antagonist 10 (78-93%). The observed binding pattern was mainly consistent with the known D 4R distribution in the rat brain. Thus, [(18)F]3h (FAUC F41) represents a potential radioligand for studying the D 4R in vivo by positron emission tomography (PET).