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In animal studies it has been observed that the inhibitory neuromodulator adenosine is released into the cerebral interstitial space during hypoxic challenges. Adenosine's actions on the A 1 adenosine receptor (A 1 AR) protect the brain from oxygen deprivation and overexertion through adjustments in cerebral blood flow, metabolism, and electric activity. Methods: Using 8-cyclopentyl-3-(3-[ 18 F]fluoropropyl)-1-propylxanthine ([ 18 F]CPFPX), a PET tracer for the A 1 AR, we tested the hypothesis that hypoxia-induced adenosine release reduces A 1 AR availability in the human brain. Furthermore, we investigated whether this response is associated with altered brain perfusion and psychomotor vigilance. Ten healthy volunteers completed a 110-min bolus-plus-constant-infusion [ 18 F]CPFPX PET/MRI hybrid experiment including a 30-min interval of normobaric hypoxia with peripheral oxygen saturation between 70% and 75%. We obtained blood samples to calculate metabolite-corrected steady-state A 1 AR distribution volumes and measured gray matter brain perfusion via arterial spin labeling in high temporal resolution. A 3-min psychomotor vigilance test was conducted every 10 min, and heart rate and peripheral blood oxygen saturation were continuously measured. Results: In all 7 examined brain regions, hypoxia reduced A 1 AR availability significantly (e.g., frontal lobe, 13.5%; P = 0.0144) whereas gray matter brain perfusion increased (e.g., frontal lobe, 42.5%; P = 0.0007). Heart rate increased by 19% ( P = 0.0039). Mean reaction speed decreased by 4.3% ( P = 0.0021). Conclusion: Our study is the first, to our knowledge, to demonstrate that acute hypoxia, corresponding to a mean altitude of 5,500 m (18,000 ft), reduces A 1 AR availability in the human brain. The finding is consistent with hypoxia-induced cerebral adenosine release leading to increased A 1 AR occupancy., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([ 18 F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([ 18 F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [ 18 F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The short half-life of existing prostate-specific membrane antigen (PSMA) tracers limits their time for internalization into tumor cells after injection, which is an essential prerequisite for robust detection of tumor lesions with low PSMA expression on PET/CT scans. Because of its longer half-life, the 89 Zr-labeled ligand 89 Zr-PSMA-DFO allows acquisition of PET scans up to 6 d after injection, thereby overcoming the above limitation. We investigated whether 89 Zr-PSMA-DFO allowed more sensitive detection of weak PSMA-positive prostate cancer lesions. Methods: We selected 14 prostate cancer patients with biochemical recurrence who exhibited no PSMA-positive lesions on a PET scan acquired with existing PSMA tracers ( 68 Ga-PSMA-11, 18 F-JK-PSMA-7). Within 5 wk after the negative scan result, we obtained a second PSMA PET scan using 89 Zr-PSMA-DFO (117 ± 16 MBq, PET acquisition within 6 d of injection). Results: 89 Zr-PSMA-DFO detected 15 PSMA-positive lesions in 8 of 14 patients, who had a PET-negative reading of their initial PET scans with existing tracers. In these 8 patients, the new scans revealed localized recurrence of disease (3/8), metastases in lymph nodes (3/8), or lesions at distant sites (2/8). On the basis of these results, patients received lesion-targeted radiotherapies (5/8), androgen deprivation therapies (2/8), or no therapy (1/8). The plausibility of 14 of 15 lesions was supported by histology, clinical follow-up after radiotherapy, or subsequent imaging. Furthermore, comparison of the 15 89 Zr-PSMA-DFO-positive lesions with their correlates on the original PET scan revealed that established tracers exhibited mild accumulation in 7 of 15 lesions; however, contrast-to-noise ratios were too low for robust detection of these lesions (contrast-to-noise ratios, 2.4 ± 3.7 for established tracers vs. 10.2 ± 8.5 for 89 Zr-PSMA-DFO, P = 0.0014). The SUV max of the 15 89 Zr-PSMA-DFO-positive lesions (11.5 ± 5.8) was significantly higher than the SUV max on the original PET scans (4.7 ± 2.8, P = 0.0001). Kidneys were the most exposed organ, with doses of 3.3 ± 0.7 mGy/MBq. The effective dose was 0.15 ± 0.04 mSv/MBq. Conclusion: In patients with weak PSMA expression, a longer period of time might be needed for ligand internalization than that offered by existing PSMA tracers to make lesions visible on PET/CT scans. Hence, 89 Zr-PSMA-DFO might be of significant benefit to patients in whom the search for weak PSMA-positive lesions is challenging. Radiation exposure should be weighed against the potential benefit of metastasis-directed therapy or salvage radiotherapy, which we initiated in 36% (5/14) of our patients based on their 89 Zr-PSMA-DFO PET scans., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Tau protein aggregations are a hallmark of amyloid-associated Alzheimer disease and some forms of non-amyloid-associated frontotemporal lobar degeneration. In recent years, several tracers for in vivo tau imaging have been under evaluation. This study investigated the ability of 18 F-flortaucipir PET not only to assess tau positivity but also to differentiate between amyloid-positive and -negative forms of neurodegeneration on the basis of different 18 F-flortaucipir PET signatures. Methods: The 18 F-flortaucipir PET data of 35 patients with amyloid-positive neurodegeneration, 19 patients with amyloid-negative neurodegeneration, and 17 healthy controls were included in a data-driven scaled subprofile model (SSM)/principal-component analysis (PCA) identifying spatial covariance patterns. SSM/PCA pattern expression strengths were tested for their ability to predict amyloid status in a receiver-operating-characteristic analysis and validated with a leave-one-out approach. Results: Pattern expression strengths predicted amyloid status with a sensitivity of 0.94 and a specificity of 0.83. A support vector machine classification based on pattern expression strengths in 2 different SSM/PCA components yielded a prediction accuracy of 98%. Anatomically, prediction performance was driven by parietooccipital gray matter in amyloid-positive patients versus predominant white matter binding in amyloid-negative patients. Conclusion: SSM/PCA-derived binding patterns of 18 F-flortaucipir differentiate between amyloid-positive and -negative neurodegenerative diseases with high accuracy. 18 F-flortaucipir PET alone may convey additional information equivalent to that from amyloid PET. Together with a perfusion-weighted early-phase acquisition ( 18 F-FDG PET-equivalent), a single scan potentially contains comprehensive information on amyloid (A), tau (T), and neurodegeneration (N) status as required by recent biomarker classification algorithms (A/T/N)., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

PET using O -(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) is useful to detect residual tumor tissue after glioma resection. Recent animal experiments detected reactive changes in 18 F-FET uptake at the rim of the resection cavity within the first 2 wk after resection of gliomas. In the present study, we evaluated pre- and postoperative 18 F-FET PET scans of glioma patients with particular emphasis on the identification of reactive changes after surgery. Methods: Forty-three patients with cerebral gliomas (9 low-grade, 34 high-grade; 9 primary tumors, 34 recurrent tumors) who had preoperative (time before surgery: median, 23 d; range, 6-44 d) and postoperative 18 F-FET PET (time after surgery: median, 14 d; range, 5-28 d) were included. PET scans (20-40 min after injection) were evaluated visually for complete or incomplete resection and compared with MRI. Changes in 18 F-FET uptake were evaluated by tumor-to-brain ratios in residual tumor and by maximum lesion-to-brain ratios near the resection cavity. Results: Visual analysis of 18 F-FET PET scans revealed complete resection in 16 of 43 patients and incomplete resection in the remaining patients. PET results were concordant with MRI in 69% of the patients. The maximum lesion-to-brain ratio for 18 F-FET uptake near the resection cavity was significantly higher than preoperative values (1.59 ± 0.36 vs. 1.14 ± 0.17; n = 43; P < 0.001). In 11 patients (26%), a flare phenomenon was observed, with a considerable increase in 18 F-FET uptake compared with preoperative values in either the residual tumor ( n = 5) or areas remote from the tumor on the preoperative PET scan ( n = 6) (2.92 ± 1.24 vs. 1.62 ± 0.75; P < 0.001). Further follow-up in 5 patients showed decreasing 18 F-FET uptake in the flare areas in 4 patients and progress in 1 patient. Conclusion: Our study confirmed that 18 F-FET PET provides valuable information for assessing the success of glioma resection. Postoperative reactive changes at the rim of the resection cavity appear to be mild. However, in 23% of the patients, a postoperative flare phenomenon was observed that warrants further investigation., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

18 F-prostate-specific membrane antigen (PSMA)-1007 is excreted mainly through the liver. We benchmarked the performance of 18 F-PSMA-1007 against 3 renally excreted PSMA tracers. Methods: Among 668 patients, we selected 27 in whom PET/CT results obtained with 68 Ga-PSMA-11, 18 F-DCFPyL (2-(3-(1-carboxy-5-[(6-[ 18 F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid), or 18 F-JK-PSMA-7 (JK, Juelich-Koeln) were interpreted as equivocal or negative or as oligometastatic disease (PET-1). Within 3 wk, a second PET scan with 18 F-PSMA-1007 was performed (PET-2). The confidence in the interpretation of PSMA-positive locoregional findings was scored on a 5-point scale, first in routine diagnostics (reader 1) and then by an independent second evaluation (reader 2). Discordant PSMA-positive skeletal findings were examined by contrast-enhanced MRI. Results: For both readers, 18 F-PSMA-1007 facilitated the interpretability of 27 locoregional lesions. In PET-2, the clinical readout led to a significantly lower number of equivocal locoregional lesions ( P = 0.024), and reader 2 reported a significantly higher rate of suspected lesions that were falsely interpreted as probably benign in PET-1 ( P = 0.023). Exclusively in PET-2, we observed a total of 15 PSMA-positive spots in the bone marrow of 6 patients (22%). None of the 15 discordant spots had a morphologic correlate on the corresponding CT scan or on the subsequent MRI scan. Thus, 18 F-PSMA-1007 exhibits a significantly higher rate of unspecific medullary spots ( P = 0.0006). Conclusion: 18 F-PSMA-1007 may increase confidence in interpreting small locoregional lesions adjacent to the urinary tract but may decrease the interpretability of skeletal lesions., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

In preclinical trials, the recently developed tracer 2-methoxy- 18 F-DCFPyL ( 18 F-JK-prostate-specific membrane antigen [PSMA]-7) has shown favorable properties regarding clinical performance and radiochemical accessibility. The aim of this study was to evaluate the clinical utility of 18 F-JK-PSMA-7 for PET/CT imaging of patients with prostate cancer. Methods: In an Institutional Review Board-approved pilot study, the initial clinical utility of PET/CT imaging with 18 F-JK-PSMA-7 was directly compared with 68 Ga-PSMA-11 PET/CT in a group of 10 patients with prostate cancer. The 2 PSMA tracers were administered to each patient less than 3 wk apart. Next, we analyzed the data of 75 consecutive patients who had undergone clinical 18 F-JK-PSMA-7 PET/CT imaging for tumor localization of biochemical recurrence (BCR). Results: The pilot study in 10 patients who were examined with both PSMA tracers demonstrated that 18 F-JK-PSMA-7 was at least equivalent to 68 Ga-PSMA-11. All unequivocally 68 Ga-PSMA-11-positive lesions could be also detected using 18 F-JK-PSMA-7, and in 4 patients additional suspected PSMA-positive lesions were identified (1 patient changed from PSMA-negative to PSMA-positive). In patients with BCR (after prostatectomy or radiotherapy), the capacity of 18 F-JK-PSMA-7 PET/CT to detect at least one PSMA-positive lesion was 84.8%. The prostate-specific antigen (PSA)-stratified detection rate of 18 F-JK-PSMA-7 after prostatectomy varied among 54.5% (6/11 patients; PSA < 0.5 μg/L), 87.5% (14/16 patients; PSA 0.5-2 μg/L), and 90.9% (20/22 patients; PSA > 2 μg/L). Conclusion: The tracer 18 F-JK-PSMA-7 was found to be safe and clinically useful. We demonstrated that 18 F-JK-PSMA-7 was not inferior when directly compared with 68 Ga-PSMA-11 in a pilot study but indeed identified additional PSMA-avid suspected lesions in oligometastasized patients with BCR. In a subsequent analysis of a clinical cohort of BCR patients, 18 F-JK-PSMA-7 was useful in tumor localization. 18 F-JK-PSMA-7 is recommended for future prospective trials., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Prostate-specific membrane antigen (PSMA), expressed by most prostate carcinomas (PCa), is a promising target for PCa imaging. The application of PSMA-specific 18 F-labeled PET probes such as 18 F-DCFPyL and 18 F-PSMA-1007 considerably improved the accuracy of PCa tumor detection. However, there remains a need for further improvements in sensitivity and specificity. The aim of this study was the development of highly selective and specific PSMA probes with enhanced imaging properties, in comparison with 18 F-DCFPyL, 18 F-PSMA-1007, and 68 Ga-PSMA-11. Methods: Eight novel 18 F-labeled PSMA ligands were prepared. Their cellular uptake in PSMA-positive LNCaP C4-2 and PSMA-negative PC-3 cells was compared with that of 18 F-DCFPyL. The most promising candidates were additionally evaluated by small-animal PET in healthy rats using PSMA-positive peripheral ganglia as a model for small PCa lesions. PET images of the ligand with the best outcome, 18 F-JK-PSMA-7, were compared with those of 18 F-DCFPyL, 18 F-PSMA-1007, and 68 Ga-PSMA-11 with respect to key image-quality parameters for the time frame 60-120 min. Results: Compared with 18 F-DCFPyL, 18 F-JK-PSMA-7 demonstrated increased PSMA-specific cellular uptake. Although target-to-background ratios of 18 F-DCFPyL and 18 F-PSMA-1007 were comparable, this parameter was higher for 18 F-JK-PSMA-7 and lower for 68 Ga-PSMA-11. Image acutance was significantly higher for 18 F-JK-PSMA-7 and 18 F-PSMA-1007 than for 18 F-DCFPyL and 68 Ga-PSMA-11. Image resolution was similar for all 4 tracers. 18 F-PSMA-1007 demonstrated significantly higher blood protein binding and bone uptake than the other tracers. Conclusion: 18 F-JK-PSMA-7 is a promising candidate for high-quality visualization of small PSMA-positive lesions. Excellent preclinical imaging properties justify further preclinical and clinical studies of this tracer., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Several studies outlined the sensitivity of 68 Ga-labeled PET tracers against the prostate-specific membrane antigen (PSMA) for localization of relapsed prostate cancer in patients with renewed increase in the prostate-specific antigen (PSA), commonly referred to as biochemical recurrence. Labeling of PSMA tracers with 18 F offers numerous advantages, including improved image resolution, longer half-life, and increased production yields. The aim of this study was to assess the PSA-stratified performance of the 18 F-labeled PSMA tracer 18 F-DCFPyL and the 68 Ga-labeled reference 68 Ga-PSMA-HBED-CC. Methods: We examined 191 consecutive patients with biochemical recurrence according to standard acquisition protocols using 18 F-DCFPyL ( n = 62, 269.8 MBq, PET scan at 120 min after injection) or 68 Ga-PSMA-HBED-CC ( n = 129, 158.9 MBq, 60 min after injection). We determined PSA-stratified sensitivity rates for both tracers and corrected our calculations for Gleason scores using iterative matched-pair analyses. As an orthogonal validation, we directly compared tracer distribution patterns in a separate cohort of 25 patients, sequentially examined with both tracers. Results: After prostatectomy ( n = 106), the sensitivity of both tracers was significantly associated with absolute PSA levels ( P = 4.3 × 10 -3 ). Sensitivity increased abruptly, when PSA values exceeded 0.5 μg/L ( P = 2.4 × 10 -5 ). For a PSA less than 3.5 μg/L, most relapses were diagnosed at a still limited stage ( P = 3.4 × 10 -6 ). For a PSA of 0.5-3.5 μg/L, PSA-stratified sensitivity was 88% (15/17) for 18 F-DCFPyL and 66% (23/35) for 68 Ga-PSMA-HBED-CC. This significant difference was preserved in the Gleason-matched-pair analysis. Outside of this range, sensitivity was comparably low (PSA < 0.5 μg/L) or high (PSA > 3.5 μg/L). After radiotherapy ( n = 85), tracer sensitivity was largely PSA-independent. In the 25 patients examined with both tracers, distribution patterns of 18 F-DCFPyL and 68 Ga-PSMA-HBED-CC were strongly comparable ( P = 2.71 × 10 -8 ). However, in 36% of the PSMA-positive patients we detected additional lesions on the 18 F-DCFPyL scan ( P = 3.7 × 10 -2 ). Conclusion: Our data suggest that 18 F-DCFPyL is noninferior to 68 Ga-PSMA-HBED-CC, while offering the advantages of 18 F labeling. Our results indicate that imaging with 18 F-DCFPyL may even exhibit improved sensitivity in localizing relapsed tumors after prostatectomy for moderately increased PSA levels. Although the standard acquisition protocols, used for 18 F-DCFPyL and 68 Ga-PSMA-HBED-CC in this study, stipulate different activity doses and tracer uptake times after injection, our findings provide a promising rationale for validation of 18 F-DCFPyL in future prospective trials., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiohalogenated agents are often the first line of pursuit in the development of new radiopharmaceuticals-whether antibodies, peptides, or small molecules-because of their ease of synthesis, lack of substantial steric perturbation of the original affinity agent (in some cases, providing enhanced affinity), and capacity to be transformed into therapeutics (in some cases, with a mere switch of an isotope). They often provide proof of a principle before optimization for pharmacokinetics or generation of radiometallated agents, when the latter are necessary. In particular, 18 F has been well integrated into normal clinical work flow in the form of 18 F-FDG for oncologic imaging, with reliable daily production and distribution to sites for immediate use, without the need for on-site preparation. Here we discuss radiohalogenated versions of imaging and therapeutic agents targeting the prostate-specific membrane antigen (PSMA); these were among the first such agents to be synthesized and used clinically. PSMA is highly expressed on prostate cancer epithelial cells and is currently being extensively investigated around the world as a target for imaging and therapy of prostate cancer. Additionally, the presence of PSMA on nonprostate tumor neovasculature has opened the possibility of PSMA-targeted molecules as generalizable cancer imaging and therapy agents. We focus on 18 F-labeled agents for PET, as they begin to redefine-along with the corresponding 68 Ga-labeled agents discussed elsewhere in this supplement to The Journal of Nuclear Medicine-the management of prostate cancer across a variety of clinical contexts., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: The hypothesis of this study was that distinct experimental glioblastoma phenotypes resembling human disease can be noninvasively distinguished at various disease stages by imaging in vivo., Methods: Cultured spheroids from 2 human glioblastomas were implanted into the brains of nude rats. Glioblastoma growth dynamics were followed by PET using (18)F-FDG, (11)C-methyl-l-methionine ((11)C-MET), and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and by MRI at 3-6 wk after implantation. For image validation, parameters were coregistered with immunohistochemical analysis., Results: Two tumor phenotypes (angiogenic and infiltrative) were obtained. The angiogenic phenotype showed high uptake of (11)C-MET and (18)F-FLT and relatively low uptake of (18)F-FDG. (11)C-MET was an early indicator of vessel remodeling and tumor proliferation. (18)F-FLT uptake correlated to positive Ki67 staining at 6 wk. T1- and T2-weighted MR images displayed clear tumor delineation with strong gadolinium enhancement at 6 wk. The infiltrative phenotype did not accumulate (11)C-MET and (18)F-FLT and impaired the (18)F-FDG uptake. In contrast, the Ki67 index showed a high proliferation rate. The extent of the infiltrative tumors could be observed by MRI but with low contrast., Conclusion: For angiogenic glioblastomas, noninvasive assessment of tumor activity corresponds well to immunohistochemical markers, and (11)C-MET was more sensitive than (18)F-FLT at detecting early tumor development. In contrast, infiltrative glioblastoma growth in the absence of blood-brain barrier breakdown is difficult to noninvasively follow by existing imaging techniques, and a negative (18)F-FLT PET result does not exclude the presence of proliferating glioma tissue. The angiogenic model may serve as an advanced system to study imaging-guided antiangiogenic and antiproliferative therapies.

Unlabelled: The purpose of this study was to evaluate the relevance for the prediction of clinical benefit of first-line treatment with erlotinib using different quantitative parameters for PET with both (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) in patients with advanced non-small cell lung cancer., Methods: Data were used from a prospective trial involving patients with untreated stage IV non-small cell lung cancer. (18)F-FDG PET and (18)F-FLT PET were performed before and 1 (early) and 6 (late) weeks after erlotinib treatment. Several quantitative standardized uptake values (SUVs) using different definitions of volumes of interest with varying isocontours (maximum SUV [SUV(max)], 2-dimensional peak SUV [SUV(2Dpeak)], 3-dimensional [3D] peak SUV [SUV(3Dpeak)], 3D isocontour at 50% of the maximum pixel value [SUV(50)], 3D isocontour at 50% adapted for background [SUV(A50)], 3D isocontour at 41% of the maximum pixel value adapted for background [SUV(A41)], 3D isocontour at 70% of the maximum pixel value [SUV(70)], 3D isocontour at 70% adapted for background [SUV(A70)], and relative SUV threshold level [SUV(RTL)]) and metabolically active volume measurements were obtained in the hottest single tumor lesion and in the sum of up to 5 lesions per scan in 30 patients. Metabolic response was defined as a minimum reduction of 30% in each of the different SUVs and as a minimum reduction of 45% in metabolically active volume. Progression-free survival (PFS) was compared between patients with and without metabolic response measured with each of the different parameters, using Kaplan-Meier statistics and a log-rank test., Results: Patients with a metabolic response on early (18)F-FDG PET and (18)F-FLT PET in the hottest single tumor lesion as well as in the sum of up to 5 lesions per scan had a significantly longer PFS, regardless of the method used to calculate SUV. However, the highest significance was obtained for SUV(max), SUV(50), SUV(A50), and SUV(A41.) Patients with a metabolic response measured by SUV(max) and SUV(3Dpeak) on late (18)F-FDG PET in the hottest single tumor lesion had a significantly longer PFS. Furthermore, Kaplan-Meier analyses showed a strong association between PFS and response seen by metabolically active volume, measured either in early (18)F-FLT or in late (18)F-FDG., Conclusion: Early (18)F-FDG PET and (18)F-FLT PET can predict PFS regardless of the method used for SUV calculation. However, SUV(max), SUV(50), SUV(A50), and SUV(A41) measured with (18)F-FDG might be the best robust SUV to use for early response prediction. Metabolically active volume measurement in early (18)F-FLT PET and late (18)F-FDG PET may have an additional predictive value in monitoring response in patients with advanced non-small cell lung cancer treated with erlotinib.

Unlabelled: Diseases and dysfunction of the central nervous system are often associated with regional changes in cerebral glucose metabolism, which can be measured in vivo by PET using (18)F-FDG as the tracer. For quantification, the arterial tracer input function must be determined. For rodents in particular, direct measurement of blood radioactivity concentration is scarcely feasible for follow-up of individual animals because of the invasiveness of blood sampling. We show that the whiskers area of the rat's muzzle serves as an extracerebral reference region. The derived model also takes into account local variations of the lumped constant, which is crucial in pathologic tissue., Methods: In 11 rats, the reference tissue kinetic parameters were determined from PET data and measured whole blood radioactivity concentration. Parametric images of cerebral kinetic rate constants were calculated using the directly measured input function, the reference tissue time-activity curve with individually fitted reference kinetic parameters, and the reference time-activity curve with fixed reference kinetic parameters calculated from the fitted parameters averaged over all animals. The need for kinetic modeling in disease models is demonstrated in 5 rats subjected to acute focal cerebral ischemia. (18)F-FDG metabolism and transport rate constants and local cerebral glucose metabolic rates were calculated., Results: Cerebral kinetic constants derived from the 3 methods corresponded closely. The maximum difference in whole-brain kinetic parameters observed between the directly measured input function and the reference tissue time-activity curve with individually fitted reference kinetic parameters was less than 5%. Taking fixed reference parameters (the reference time-activity curve with fixed reference kinetic parameters calculated from the fitted parameters averaged over all animals) still provided whole-brain kinetic parameters with an accuracy of approximately 90%. In the rats subjected to focal cerebral ischemia, (18)F-FDG kinetic parameters in healthy tissue were not significantly different from whole-brain kinetic parameters in naive rats. The ischemic region was characterized by preserved glucose metabolism, although (18)F-FDG uptake was elevated significantly-that is, the lumped constant in the ischemic region was different from that of healthy brain tissue., Conclusion: The method presented here allows for the quantitative noninvasive determination of cerebral glucose consumption in rats, takes into account local variations of the lumped constant, and is suitable for follow-up measurements of individuals.

Unlabelled: The outcome of hematopoietic cell transplantation for hematologic malignancies may be improved by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the biodistribution of 111In-labeled anti-CD45 antibody in humans using the rat IgG2a monoclonal antibody YAML568 that recognizes a common CD45 epitope present on all human leukocytes., Methods: Eight patients undergoing bone marrow transplantation received YAML568 labeled with 122 +/- 16 MBq of 111In intravenously followed by serial blood sampling, urine collection, and conjugated view planar gamma-camera imaging up to 144 h after injection. Time-activity curves were obtained using region-of-interest analysis in the accumulating organs and residence times were calculated. An estimate for the radiation-absorbed doses for each organ per unit of administered activity of 90Y was calculated using software for internal dose assessment. The first patient received no unlabeled antibody preloading. The second 2 patients received a preloading dose of 10 mg (0.15 mg/kg). The last 5 patients received a preloading dose of 30-47 mg (0.5 mg/kg)., Results: No significant administration-related side effects were seen. The 3 patients receiving no antibody or low antibody preloading had an unfavorable biodistribution with a high initial accumulation of activity in the liver (37%) and the spleen (34%). For the patients receiving 0.5-mg/kg antibody preloading, the estimated radiation-absorbed doses for red bone marrow, spleen, liver, kidney, and total body were 6.4 +/- 1.2, 19 +/- 5, 3.9 +/- 1.4, 1.1 +/- 0.4, and 0.6 +/- 0.1 mGy/MBq, respectively, demonstrating preferential red marrow targeting. A linear regression model showed that the amount of unlabeled antibody preloading per body weight has a strong influence on the estimated red marrow absorbed dose (P = 0.003, R2 = 0.80)., Conclusion: This study shows that the anti-CD45 monoclonal antibody YAML568 is suitable for delivering selectively radiation to hematopoietic tissues when labeled with 90Y provided that a preloading dose of about 0.5 mg/kg unlabeled antibody is given.

Unlabelled: The ability of 11C-choline and multimodality fusion imaging with integrated PET and contrast-enhanced CT (PET/CT) was investigated to delineate prostate carcinoma (PCa) within the prostate and to differentiate cancer tissue from normal prostate, benign prostate hyperplasia, and focal chronic prostatitis., Methods: All patients with PCa gave written informed consent. Twenty-six patients with clinical stage T1, T2, or T3 and biopsy-proven PCa underwent 11C-choline PET/CT after intravenous injection of 1,112 +/- 131 MBq 11C-choline, radical retropubic prostatovesiculectomy, and standardized prostate tissue sampling. Maximal standardized uptake values (SUVs) of 11C-choline within 36 segments of the prostate were determined. PET/CT results were correlated with histopathologic results, prostate-specific antigen (PSA), Gleason score, and pT stage., Results: The SUV of 11C-choline in PCa tissue was 3.5 +/- 1.3 (mean +/- SD) and significantly higher than that in prostate tissue with benign histopathologic lesions (2.0 +/- 0.6; P < 0.001 benign histopathology vs. cancer). Visual and quantitative analyses of segmental 11C-choline uptake of each patient unambiguously located PCa in 26 of 26 patients and 25 of 26 patients, respectively. A threshold SUV of 2.65 yielded an area under the receiver-operating-characteristic (ROC) curve of 0.89 +/- 0.01 for correctly locating PCa. The maximal 11C-choline SUV did not correlate significantly with PSA or Gleason score but did correlate with T stage (P = 0.01; Spearman r = 0.49)., Conclusion: 11C-Choline PET/CT can accurately detect and locate major areas with PCa and differentiate segments with PCa from those with benign hyperplasia, chronic prostatitis, or normal prostate tissue. The maximal tumoral 11C-choline uptake is related to pT stage.

Unlabelled: Intensification of the conditioning regimen with a radioactively labeled anti-CD66 antibody is feasible before allogeneic stem cell transplantation. The use of radioimmunotherapy may deliver a significant dose of radiation to the kidneys. We therefore studied the incidence and clinical picture of bone marrow transplantation (BMT) nephropathy in our patients receiving radioimmunotherapy before allogeneic stem cell transplantation., Methods: This study was a clinical trial of 114 consecutive patients who received conditioning with a radiolabeled anti-CD66 antibody-188Re (n = 93) or 90Y (n = 21)-between 1998 and 2003., Results: Although BMT nephropathy has developed in none of the patients in the [90Y]anti-CD66 group, 6 of 93 patients receiving [188Re]anti-CD66 presented with signs of BMT nephropathy at a median of 11.5 mo after stem cell transplantation. The absorbed renal dose was significantly lower in the 90Y group (4 vs. 7 Gy, P < 0.0001). Of the patients receiving [188Re]anti-CD66 who are alive, BMT nephropathy developed in 19% (6/32). Five of 6 patients with BMT nephropathy received total-body irradiation. The patients presented with elevated serum creatinine, proteinuria, anemia, hypertension, and signs of microangiopathy. All 6 patients in whom BMT nephropathy has developed are alive at a median follow-up of 58 mo after stem cell transplantation, and 1 patient has entered a dialysis program., Conclusion: BMT nephropathy appears to be a significant problem after allogeneic stem cell transplantation with intensified conditioning using the 188Re-labeled anti-CD66 applied in this study, particularly when combined with total-body irradiation.

Unlabelled: Recently, the thymidine analog 3'-deoxy-3'-(18)F-fluorothymidine (FLT) was suggested for imaging tumoral proliferation. In this prospective study, we examined whether (18)F-FLT better determines proliferative activity in newly diagnosed lung nodules than does (18)F-FDG., Methods: Twenty-six patients with pulmonary nodules on chest CT were examined with PET and the tracers (18)F-FDG and (18)F-FLT. Tumoral uptake was determined by calculation of standardized uptake value (SUV). Within 2 wk, patients underwent resective surgery or had core biopsy. Proliferative activity was estimated by counting nuclei stained with the Ki-67-specific monoclonal antibody MIB-1 per total number of nuclei in representative tissue specimens. The correlation between the percentage of proliferating cells and the SUVs for (18)F-FLT and (18)F-FDG was determined using linear regression analysis., Results: Eighteen patients had malignant tumors (13 with non-small cell lung cancer [NSCLC], 1 with small cell lung cancer, and 4 with pulmonary metastases from extrapulmonary tumors); 8 had benign lesions. In all visible lesions, mean (18)F-FDG uptake was 4.1 (median, 4.4; SD, 3.0; range, 1.0-10.6), and mean (18)F-FLT uptake was 1.8 (median, 1.2; SD, 2.0; range, 0.8-6.4). Statistical analysis revealed a significantly higher uptake of (18)F-FDG than of (18)F-FLT (Mann-Whitney U test, P < 0.05). (18)F-FLT SUV correlated better with proliferation index (P < 0.0001; r = 0.92) than did (18)F-FDG SUV (P < 0.001; r = 0.59). With the exception of 1 carcinoma in situ, all malignant tumors showed increased (18)F-FDG PET uptake. (18)F-FLT PET was false-negative in the carcinoma in situ, in another NSCLC with a low proliferation index, and in a patient with lung metastases from colorectal cancer. Increased (18)F-FLT uptake was related exclusively to malignant tumors. By contrast, (18)F-FDG PET was false-positive in 4 of 8 patients with benign lesions., Conclusion: (18)F-FLT uptake correlates better with proliferation of lung tumors than does uptake of (18)F-FDG and might be more useful as a selective biomarker for tumor proliferation.

Unlabelled: A new concept is the intensification of preparative regimens for patients with advanced leukemia using monoclonal antibodies (MAbs) with an affinity for beta emitter-labeled bone marrow. 188Re is a high-energy beta emitter that has therapeutic promise. Our first aim was to clarify whether the therapeutic application of 188Re-MAb against nonspecific cross-reacting antigen 95 (NCA-95) can be predicted from biokinetic data derived from 99mTc-labeled NCA-95. Our second aim was to show that a radiation absorbed dose of > or =12 Gy in the bone marrow can be achieved using 188Re-MAb., Methods: Dosimetric data were obtained for both radiotracers from multiple planar whole-body scans (double-head gamma camera), blood samples, and urine measurements from 12 patients with advanced leukemia. Radiation absorbed doses were calculated using MIRDOSE 3 software., Results: Radiation absorbed doses to bone marrow, liver, spleen, lung, and kidney were 2.24, 0.50, 1.93, 0.05, and 0.90 mGy/MBq, respectively, using 99mTc-MAb and 1.45, 0.43, 1.32, 0.07, and 0.71 mGy/MBq, respectively, using 188Re-MAb. These differences were statistically significant for bone marrow, spleen, and kidney. The main differences were less accumulation of 188Re-MAb in bone marrow (31%+/-13% compared with 52%+/-13%) and faster elimination through urine (25%+/-3% compared with 15%+/-5% after 24 h). On the basis of these data, a mean marrow dose of 14+/-7 Gy was achieved in 12 patients suffering from leukemia after application of approximately 10+/-2 GBq 188Re-MAb., Conclusion: Myeloablative radiation absorbed doses can easily be achieved using 188Re-MAb. 99mTc- and 188Re-MAb showed similar whole-body distributions. However, direct prediction of radiation absorbed doses from the 99mTc-MAb, assuming identical biokinetic behavior, is not valid for the 188Re-MAb in a single patient. Therefore, individual dosimetry using 188Re-MAb is needed to calculate therapeutic activity.

Unlabelled: Radionuclide bone scanning (RNB) is considered to be the most practical screening technique for assessing the entire skeleton for skeletal metastases. However, RNB has been shown to be of lower sensitivity than MRI and CT in detecting osteolytic metastases. A prospective study was designed to evaluate the accuracy of planar RNB versus tomographic bone imaging with 18F-labeled NaF and PET (18F PET) in detecting osteolytic and osteoblastic metastases and its dependency on their anatomic localization., Methods: Forty-four patients with known prostate, lung or thyroid carcinoma were examined with both planar RNB and 18F PET. A panel of reference methods including MRI of the spine, 1311 scintigraphy, conventional radiography and spiral CT was used as the gold standard. RNB and 18F PET were compared by a lesion-by-lesion analysis using a five-point score for receiver operating characteristic (ROC) curve analysis., Results: 18F PET showed 96 metastases (67 of prostate carcinoma and 29 of lung or thyroid cancer), whereas RNB revealed 46 metastases (33 of prostate carcinoma and 13 of lung or thyroid cancer). All lesions found with RNB were also detected with 18F PET. Compared with 18F PET and the reference methods, RNB had a sensitivity of 82.8% in detecting malignant and benign osseous lesions in the skull, thorax and extremities and a sensitivity of 40% in the spine and pelvis. The area under the ROC curve was 0.99 for 18F PET and 0.64 for RNB., Conclusion: 18F PET is more sensitive than RNB in detecting osseous lesions. With RNB, sensitivity in detecting osseous metastases is highly dependent on anatomic localization of these lesions, whereas detection rates of osteoblastic and osteolytic metastases are similar. Higher detection rates and more accurate differentiation between benign and malignant lesions with 18F PET suggest the use of 18F PET when possible.