Comparing Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen-Positron Emission Tomography for Prediction of Extraprostatic Extension of Prostate Cancer and Surgical Guidance: A Prospective Nonrandomized Clinical Trial.

PURPOSE: Survivors of surgically managed prostate cancer may experience urinary incontinence and erectile dysfunction. Our aim was to determine if 68Ga-prostate-specific membrane antigen-11 positron emission tomography CT (PSMA-PET) in addition to multiparametric (mp) MRI scans improved surgical decision-making for nonnerve-sparing or nerve-sparing approach. MATERIALS AND METHODS: We prospectively enrolled 50 patients at risk for extraprostatic extension (EPE) who were scheduled for prostatectomy. After mpMRI and PSMA-PET images were read for EPE prediction, surgeons prospectively answered questionnaires based on mpMRI and PSMA-PET scans on the decision for nerve-sparing or nonnerve-sparing approach. Final whole-mount pathology was the reference standard. Sensitivity, specificity, positive predictive value, negative predictive value, and receiver operating characteristic curves were calculated and McNemar's test was used to compare imaging modalities. RESULTS: The median age and PSA were 61.5 years and 7.0 ng/dL. The sensitivity for EPE along the posterior neurovascular bundle was higher for PSMA-PET than mpMRI (86% vs 57%, P = .03). For MRI, the specificity, positive predictive value, negative predictive value, and area under the curve for the receiver operating characteristic curves were 77%, 40%, 87%, and 0.67, and for PSMA-PET were 73%, 46%, 95%, and 0.80. PSMA-PET and mpMRI reads differed on 27 nerve bundles, with PSMA-PET being correct in 20 cases and MRI being correct in 7 cases. Surgeons predicted correct nerve-sparing approach 74% of the time with PSMA-PET scan in addition to mpMRI compared to 65% with mpMRI alone (P = .01). CONCLUSIONS: PSMA-PET scan was more sensitive than mpMRI for EPE along the neurovascular bundles and improved surgical decisions for nerve-sparing approach. Further study of PSMA-PET for surgical guidance is warranted in the unfavorable intermediate-risk or worse populations. CLINICALTRIALS.GOV IDENTIFIER: NCT04936334.

Advanced imaging techniques for neuro-oncologic tumor diagnosis, with an emphasis on PET-MRI imaging of malignant brain tumors.

PURPOSE OF REVIEW: This review will explore the latest in advanced imaging techniques, with a focus on the complementary nature of multiparametric, multimodality imaging using magnetic resonance imaging (MRI) and positron emission tomography (PET). RECENT FINDINGS: Advanced MRI techniques including perfusion-weighted imaging (PWI), MR spectroscopy (MRS), diffusion-weighted imaging (DWI), and MR chemical exchange saturation transfer (CEST) offer significant advantages over conventional MR imaging when evaluating tumor extent, predicting grade, and assessing treatment response. PET performed in addition to advanced MRI provides complementary information regarding tumor metabolic properties, particularly when performed simultaneously. 18F-fluoroethyltyrosine (FET) PET improves the specificity of tumor diagnosis and evaluation of post-treatment changes. Incorporation of radiogenomics and machine learning methods further improve advanced imaging. The complementary nature of combining advanced imaging techniques across modalities for brain tumor imaging and incorporating technologies such as radiogenomics has the potential to reshape the landscape in neuro-oncology.

Prostate Specific Membrane Antigen Targeted Positron Emission Tomography of Primary Prostate Cancer: Assessing Accuracy with Whole Mount Pathology.

PURPOSE: We evaluated which lesions are detected and missed on [68Ga]Ga-PSMA (prostate specific membrane antigen)-11 positron emission tomography in patients with primary prostate cancer. MATERIALS AND METHODS: Patients undergoing radical prostatectomy were enrolled in this prospective observational study. Patients underwent [68Ga]Ga-PSMA-11 positron emission tomography/computerized tomography or positron emission tomography/magnetic resonance imaging prior to surgery and received a dose of [68Ga]Ga-PSMA-11 intraoperatively for positron emission tomography of extirpated specimens. Whole mount pathology was performed with lesion and intralesion based analysis to determine the characteristics of lesions detected or not detected by PSMA positron emission tomography. Lesion volume was determined by planimetry and clinically significant lesion volume was calculated as lesion volume × fraction pattern 4/5. RESULTS: On whole mount analysis 30 cancerous lesions were found in a total of 15 patients, including 4, 15, 4, 1 and 6 which were Grade Group 1, 2, 3, 4 and 5, respectively. PSMA-positron emission tomography detected 100% of primary/index lesions and 8 of 11 (82%) secondary lesions. All Grade Group 3-5 lesions were detected vs 12 of 15 Grade Group 2 lesions. When comparing Grade Group 2 vs 3-5, lesion size was similar (p=0.48) but the standardized uptake value was lower for Grade Group 2 vs 3-5 (5.3 vs 7.9, p=0.03). The 3 missed lesions showed 10% or less of pattern 4 and a Gleason pattern 4/5 volume of less than 0.1 cm3. CONCLUSIONS: PSMA positron emission tomography detected 100% of primary/index lesions in this study. The 3 missed secondary lesions were small and had a low percent of pattern 4. This argues for further study to better understand what defines clinically significant prostate cancer, which would assist in determining whether small lesions that become challenging to detect by [68Ga]Ga-PSMA-11 positron emission tomography confer a risk to the patient.

Synthesis and in vitro biological evaluation of new P2X7R radioligands [11C]halo-GSK1482160 analogs.

The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45-93% yields. The target tracers [11C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [11C]CH3OTf under basic conditions (NaOH-Na2CO3, solid, w/w 1:2) through N-[11C]methylation and isolated by HPLC combined with SPE in 40-50% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity (AM) at end of bombardment (EOB) was 370-740 GBq/µmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively.

Synthesis and preliminary biological evaluation of a novel P2X7R radioligand [18F]IUR-1601.

The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoroethylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 12% in three steps. The target tracer [18F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[18F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from desmethyl-GSK1482160 with 2-[18F]fluoroethyl tosylate, prepared from 1,2-ethylene glycol-bis-tosylate and K[18F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 1-3% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74-370 GBq/µmol. The potency of IUR-1601 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for IUR-1601 and GSK1482160 are 4.31 and 5.14 nM, respectively.

Synthesis and preliminary biological evaluation of [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate for the fractalkine receptor (CX3CR1).

The reference standard methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate (5) and its precursor 2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucine (6) were synthesized from 6-amino-2-mercaptopyrimidin-4-ol and BnBr with overall chemical yield 7% in five steps and 4% in six steps, respectively. The target tracer [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate ([11C]5) was prepared from the acid precursor with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370-1110GBq/µmol with a total synthesis time of ∼40-min from EOB. The radioligand depletion experiment of [11C]5 did not display specific binding to CX3CR1, and the competitive binding assay of ligand 5 found much lower CX3CR1 binding affinity.

Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor.

P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer's disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5-BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 30-50% decay corrected radiochemical yields with 370-1110GBq/µmol specific activity at EOB. 5-(3-[18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5-BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5-25% decay corrected radiochemical yields with 111-740GBq/µmol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5-BDBD.

Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney.

The metabolic status of the kidney is a determinant of injury susceptibility and a measure of progression for many disease processes; however, noninvasive modalities to assess kidney metabolism are lacking. In this study, we employed positron emission tomography (PET) and intravital multiphoton microscopy (MPM) to assess cortical and proximal tubule glucose tracer uptake, respectively, following experimental perturbations of kidney metabolism. Applying dynamic image acquisition PET with 2-18fluoro-2-deoxyglucose (18F-FDG) and tracer kinetic modeling, we found that an intracellular compartment in the cortex of the kidney could be distinguished from the blood and urine compartments in animals. Given emerging literature that the tumor suppressor protein p53 is an important regulator of cellular metabolism, we demonstrated that PET imaging was able to discern a threefold increase in cortical 18F-FDG uptake following the pharmacological inhibition of p53 in animals. Intravital MPM with the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) provided increased resolution and corroborated these findings at the level of the proximal tubule. Extending our observation of p53 inhibition on proximal tubule glucose tracer uptake, we demonstrated by intravital MPM that pharmacological inhibition of p53 diminishes mitochondrial potential difference. We provide additional evidence that inhibition of p53 alters key metabolic enzymes regulating glycolysis and increases intermediates of glycolysis. In summary, we provide evidence that PET is a valuable tool for examining kidney metabolism in preclinical and clinical studies, intravital MPM is a powerful adjunct to PET in preclinical studies of metabolism, and p53 inhibition alters basal kidney metabolism.

GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP.

Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.

Synthesis of [(11)C]GSK1482160 as a new PET agent for targeting P2X(7) receptor.

The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from L-pyroglutamic acid, methyl L-pyroglutamate and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 27-28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [(11)C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [(11)C]CH3OTf through N-[(11)C]methylation and isolated by HPLC combined with SPE in 40-50% and 30-40% radiochemical yield, respectively, based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/µmol with a total synthesis time of ∼40-min from EOB.

Microsphere localization and dose quantification using positron emission tomography/CT following hepatic intraarterial radioembolization with yttrium-90 in patients with advanced hepatocellular carcinoma.

PURPOSE: To characterize the distribution of absorbed radiation dose after glass microsphere radioembolization for hepatocellular carcinoma (HCC) using yttrium-90 ((90)Y) positron emission tomography/computed tomography (PET/CT). MATERIALS AND METHODS: In this retrospective study, 64 (90)Y PET/CT scans performed after treatment were evaluated following (90)Y glass-bead radioembolization in patients with advanced HCC. The intended dose to the target volume ranged from 83-129 Gy. Three-dimensional "dose maps" were created from reconstructed PET images using a voxel-based S-value transformation. Liver parenchyma and liver tumors were contoured on cross-sectional imaging and aligned with the created dose maps. RESULTS: There were 113 tumors examined as part of 64 lobar treatments. The average tumor size was 4.8 cm ± 4.0 with an average tumor dose of 173 Gy ± 109. The average dose to the nontumor parenchyma within the target volume was 93.4 Gy ± 32.6, with on average 50% of the parenchymal voxels receiving > 79 Gy ± 23 and 10% receiving > 173 Gy ± 55. The average and median tumor-to-parenchymal weighted dose ratios were 2.2 and 1.9, respectively. CONCLUSIONS: Using recommended dosimetry and administration techniques for lobar glass microsphere radioembolization, high doses to target tumors as well as background parenchyma were achieved on average with modest preferential uptake within tumors. There was wide variation in measured tumor and parenchymal doses after hepatic radioembolization for HCC, suggesting the need for continued development of patient-specific dosimetry.

A Comparison of Arterial Input Function Interpolation Methods for Patlak Plot Analysis of 68Ga-PSMA-11 PET Prostate Cancer Studies.

Positron emission tomography (PET) imaging enables quantitative assessment of tissue physiology. Dynamic pharmacokinetic analysis of PET images requires accurate estimation of the radiotracer plasma input function to derive meaningful parameter estimates, and small discrepancies in parameter estimation can mimic subtle physiologic tissue variation. This study evaluates the impact of input function interpolation method on the accuracy of Patlak kinetic parameter estimation through simulations modeling the pharmacokinetic properties of [68Ga]-PSMA-11. This study evaluated both trained and untrained methods. Although the mean kinetic parameter accuracy was similar across all interpolation models, the trained node weighting interpolation model estimated accurate kinetic parameters with reduced overall variability relative to standard linear interpolation. Trained node weighting interpolation reduced kinetic parameter estimation variance by a magnitude approximating the underlying physiologic differences between normal and diseased prostatic tissue. Overall, this analysis suggests that trained node weighting improves the reliability of Patlak kinetic parameter estimation for [68Ga]-PSMA-11 PET.

Comparison of tracer kinetic models for 68Ga-PSMA-11 PET in intermediate-risk primary prostate cancer patients.

BACKGROUND: 68Ga-PSMA-11 positron emission tomography enables the detection of primary, recurrent, and metastatic prostate cancer. Regional radiopharmaceutical uptake is generally evaluated in static images and quantified as standard uptake values (SUVs) for clinical decision-making. However, analysis of dynamic images characterizing both tracer uptake and pharmacokinetics may offer added insights into the underlying tissue pathophysiology. This study was undertaken to evaluate the suitability of various kinetic models for 68Ga-PSMA-11 PET analysis. Twenty-three lesions in 18 patients were included in a retrospective kinetic evaluation of 55-min dynamic 68Ga-PSMA-11 pre-prostatectomy PET scans from patients with biopsy-demonstrated intermediate- to high-risk prostate cancer. Three kinetic models-a reversible one-tissue compartment model, an irreversible two-tissue compartment model, and a reversible two-tissue compartment model, were evaluated for their goodness of fit to lesion and normal reference prostate time-activity curves. Kinetic parameters obtained through graphical analysis and tracer kinetic modeling techniques were compared for reference prostate tissue and lesion regions of interest. RESULTS: Supported by goodness of fit and information loss criteria, the irreversible two-tissue compartment model optimally fit the time-activity curves. Lesions exhibited significant differences in kinetic rate constants (K1, k2, k3, Ki) and semiquantitative measures (SUV and %ID/kg) when compared with reference prostatic tissue. The two-tissue irreversible tracer kinetic model was consistently appropriate across prostatic zones. CONCLUSIONS: An irreversible tracer kinetic model is appropriate for dynamic analysis of 68Ga-PSMA-11 PET images. Kinetic parameters estimated by Patlak graphical analysis or full compartmental analysis can distinguish tumor from normal prostate tissue.

Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus.

Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial.

BACKGROUND: Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. METHODS: Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. FINDINGS: Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). INTERPRETATION: Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. FUNDING: Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

Comparison of Tracer Kinetic Models for 68Ga-PSMA-11 PET in Intermediate Risk Primary Prostate Cancer Patients.

BACKGROUND: 68Ga-PSMA-11 positron emission tomography enables the detection of primary, recurrent, and metastatic prostate cancer. Regional radiopharmaceutical uptake is generally evaluated in static images and quantified as standard uptake values (SUV) for clinical decision-making. However, analysis of dynamic images characterizing both tracer uptake and pharmacokinetics may offer added insights into the underlying tissue pathophysiology. This study was undertaken to evaluate the suitability of various kinetic models for 68Ga-PSMA-11 PET analysis. Twenty-three lesions in 18 patients were included in a retrospective kinetic evaluation of 55-minute dynamic 68Ga-PSMA-11 pre-prostatectomy PET scans from patients with biopsy-demonstrated intermediate to high-risk prostate cancer. A reversible one-tissue compartment model, irreversible two-tissue compartment model, and a reversible two-tissue compartment model were evaluated for their goodness-of-fit to lesion and normal reference prostate time-activity curves. Kinetic parameters obtained through graphical analysis and tracer kinetic modeling techniques were compared for reference prostate tissue and lesion regions of interest. RESULTS: Supported by goodness-of-fit and information loss criteria, the irreversible two-tissue compartment model was selected as optimally fitting the time-activity curves. Lesions exhibited significant differences in kinetic rate constants (K1, k2, k3, Ki) and semiquantitative measures (SUV) when compared with reference prostatic tissue. The two-tissue irreversible tracer kinetic model was consistently appropriate across prostatic zones. CONCLUSIONS: An irreversible tracer kinetic model is appropriate for dynamic analysis of 68Ga-PSMA-11 PET images. Kinetic parameters estimated by Patlak graphical analysis or full compartmental analysis can distinguish tumor from normal prostate tissue.

Assessing extra-prostatic extension for surgical guidance in prostate cancer: Comparing two PSMA-PET tracers with the standard-of-care.

BACKGROUND: Incontinence and impotence occur following radical prostatectomy due to injury to nerves and sphincter muscle. Preserving nerves and muscle adjacent to prostate cancer risks positive surgical margins. Advanced imaging with MRI has improved cancer localization but limitations exist. OBJECTIVE: To measure the accuracy for assessing extra-prostatic extension at nerve bundles for 2 PSMA-PET tracers and to compare the PET accuracy to standard-of-care predictors including MRI and biopsy results. MATERIALS AND METHODS: We studied men with PSMA-targeted PET imaging, performed prior to prostatectomy in men largely with intermediate to high-risk prostate cancer, and retrospectively evaluated for assessment of extra-prostatic extension with whole-mount analysis as reference standard. Two different PSMA-PET tracers were included: 68Ga-PSMA-11 and 68Ga-P16-093. Blinded reviews of the PET and MRI scans were performed to assess extra-prostatic extension (EPE). Sensitivity and specificity for extra-prostatic extension were compared using McNemar's Chi2. RESULTS: Pre-operative PSMA-PET imaging was available for 71 patients with either 68Ga-P16-093 (n = 25) or 68Ga-PSMA-11 (n = 46). There were 24 (34%) with pT3a (EPE) and 16 (23%) with pT3b (SVI). EPE Sensitivity (87% vs. 92%), Specificity (77% vs. 76%), and ROC area (0.82 vs. 0.84) were similar between P16-093 and PSMA-11, respectively (P = 0.87). MRI (available in only 45) found high specificity (83%) but low sensitivity (60%) for EPE when using a published grading system. MRI sensitivity was significantly lower than the PSMA-PET (60% vs. 90%, P = 0.02), but similar to PET when using a >5 mm capsular contact (76% vs. 90%, P = 0.38). A treatment change to "nerve sparing" was recommended in 21 of 71 (30%) patients based on PSMA-PET imaging. CONCLUSIONS: Presurgical PSMA-PET appeared useful as a tool for surgical planning, changing treatment plans in men with ≥4+3 or multi-core 3+4 prostate cancer resulting in preservation of nerve-bundles.

Hybrid 18F-Fluoroethyltyrosine PET and MRI with Perfusion to Distinguish Disease Progression from Treatment-Related Change in Malignant Brain Tumors: The Quest to Beat the Toughest Cases.

Conventional MRI has important limitations when assessing for progression of disease (POD) versus treatment-related changes (TRC) in patients with malignant brain tumors. We describe the observed impact and pitfalls of implementing 18F-fluoroethyltyrosine (18F-FET) perfusion PET/MRI into routine clinical practice. Methods: Through expanded-access investigational new drug use of 18F-FET, hybrid 18F-FET perfusion PET/MRI was performed during clinical management of 80 patients with World Health Organization central nervous system grade 3 or 4 gliomas or brain metastases of 6 tissue origins for which the prior brain MRI results were ambiguous. The diagnostic performance with 18F-FET PET/MRI was dually evaluated within routine clinical service and for retrospective parametric evaluation. Various 18F-FET perfusion PET/MRI parameters were assessed, and patients were monitored for at least 6 mo to confirm the diagnosis using pathology, imaging, and clinical progress. Results: Hybrid 18F-FET perfusion PET/MRI had high overall accuracy (86%), sensitivity (86%), and specificity (87%) for difficult diagnostic cases for which conventional MRI accuracy was poor (66%). 18F-FET tumor-to-brain ratio static metrics were highly reliable for distinguishing POD from TRC (area under the curve, 0.90). Dynamic tumor-to-brain intercept was more accurate (85%) than SUV slope (73%) or time to peak (73%). Concordant PET/MRI findings were 89% accurate. When PET and MRI conflicted, 18F-FET PET was correct in 12 of 15 cases (80%), whereas MRI was correct in 3 of 15 cases (20%). Clinical management changed after 88% (36/41) of POD diagnoses, whereas management was maintained after 87% (34/39) of TRC diagnoses. Conclusion: Hybrid 18F-FET PET/MRI positively impacted the routine clinical care of challenging malignant brain tumor cases at a U.S. institution. The results add to a growing body of literature that 18F-FET PET complements MRI, even rescuing MRI when it fails.

A new facile synthetic route to [11C]GSK189254, a selective PET radioligand for imaging of CNS histamine H3 receptor.

GSK189254 and its corresponding precursor GSK185071B were synthesized from 3-methoxyphenylacetic acid with 6-chloropyridine-3-carbolic acid or 6-chloronicotinamide in 8 and 7 steps with either 6% or 7% and either 14% or 16% yield, respectively. [(11)C]GSK189254 was prepared from GSK185071B with [(11)C]CH(3)OTf through N-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 50-60% radiochemical yield based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB), with 370-740 GBq/µmol specific activity at EOB.

In Vivo Quantitative Whole-Body Perfusion Imaging Using Radiolabeled Copper(II) Bis(Thiosemicarbazone) Complexes and Positron Emission Tomography (PET).

Traditional quantitative perfusion imaging methods require complex data acquisition and analysis strategies; typically require ancillary arterial blood sampling for measurement of input functions; are limited to single organ or tissue regions in an imaging session; and because of their complexity, are not well suited for routine clinical implementation in a standardized fashion that can be readily repeated across diverse clinical sites. The whole-body perfusion method described in this chapter has the advantages of on-demand radiotracer production; simple tissue pharmacokinetics enabling standardized estimation of perfusion; short-lived radionuclides, facilitating repeat or combination imaging procedures; and scalability to support widespread clinical implementation. This method leverages the unique physiological characteristics of radiolabeled copper(II) bis(thiosemicarbazone) complexes and the detection sensitivity of positron emission tomography (PET) to produce quantitatively accurate whole-body perfusion images. This chapter describes the synthesis of ethylglyoxal bis(thosemicarbazonato)copper(II) labeled with copper-62 ([62Cu]Cu-ETS), its unique physiological characteristics, a simple tracer kinetic model for estimation of perfusion using image-derived input functions, and validation of the method against a reference standard perfusion tracer. A detailed description of the methods is provided to facilitate implementation of the perfusion imaging method in PET imaging facilities.