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Background Integrated PET/MRI is a promising modality for breast assessment. The most frequently used tracer, fluorine 18 ( 18 F) fluorodeoxyglucose (FDG), is applied for whole-body staging in advanced breast cancer but has limited accuracy in evaluating primary breast lesions. The fibroblast-activation protein (FAP) is abundantly expressed in invasive breast cancer. FAP-directed PET tracers have recently become available, but results in primary breast tumors remain lacking. Purpose To evaluate the use of FAP inhibitor (FAPI) breast PET/MRI in assessing breast lesions and of FAPI whole-body scanning for lymph node (LN) and distant staging using the ligand gallium 68 ( 68 Ga)-FAPI-46. Materials and Methods In women with histologically confirmed invasive breast cancer, all primary 68 Ga-FAPI-46 breast and whole-body PET/MRI and PET/CT examinations conducted at the authors' center between October 2019 and December 2020 were retrospectively analyzed. MRI lesion characteristics and standardized uptake values (SUVs) were quantified with dedicated software. Mann-Whitney U tests were used to compare tumor SUVs across different tumor types. The Pearson correlation coefficient was calculated between SUV and measures of MRI morphologic characteristics. Results Nineteen women (mean age, 49 years ± 9 [standard deviation]) were evaluated-18 to complement initial staging and one for restaging after therapy for distant metastases. Strong tracer accumulation was observed in all 18 untreated primary breast malignancies (mean maximum SUV [SUV max ] = 13.9 [range, 7.9-29.9]; median lesion diameter = 26 mm [range, 9-155 mm]), resulting in clear tumor delineation across different gradings, receptors, and histologic types. All preoperatively verified LN metastases in 13 women showed strong tracer accumulation (mean SUV max = 12.2 [range, 3.3-22.4]; mean diameter = 21 mm [range, 14-35 mm]). Tracer uptake established or supported extra-axillary LN involvement in seven women and affected therapy decisions in three women. Conclusion This retrospective analysis indicates use of 68 Ga fibroblast-activation protein inhibitor tracers for breast cancer diagnosis and staging. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Mankoff and Sellmyer in this issue.

Background: Graft versus host disease (GvHD) is a frequent complication of allogeneic stem cell transplantation (alloSCT), significantly increasing mortality. Previous imaging studies focused on the assessment of intestinal GvHD with contrast-enhanced MRI/CT or 18 F-FDG-PET imaging alone. The objective of this retrospective study was to elucidate the diagnostic value of a combined 18 F-FDG-PET-MRI protocol in patients with acute intestinal GvHD., Methods: Between 2/2015 and 8/2019, 21 patients with acute intestinal GvHD underwent 18 F-FDG-PET-MRI. PET, MRI and PET-MRI datasets were independently reviewed. Readers assessed the number of affected segments of the lower gastrointestinal tract and the reliability of the diagnosis on a 5-point Likert scale and quantitative PET (SUVmax, SUVpeak, metabolic volume (MV)) and MRI parameter (wall thickness), were correlated to clinical staging of acute intestinal GvHD., Results: The detection rate for acute intestinal GvHD was 56.8% for PET, 61.4% for MRI and 100% for PET-MRI. PET-MRI (median Likert-scale value: 5; range: 4-5) offers a significantly higher reliability of the diagnosis compared to PET (median: 4; range: 2-5; p = 0.01) and MRI alone (median: 4; range: 3-5; p = 0.03). The number of affected segments in PET-MRI (r s  = 0.677; p <  0.001) and the MV (r s  = 0.703; p <  0.001) correlated significantly with the clinical stage. SUVmax (r s  = 0.345; p = 0.14), SUVpeak (r s  = 0.276; p = 0.24) and wall thickening (r s  = 0.174; p = 0.17) did not show a significant correlation to clinical stage., Conclusion: 18 F-FDG-PET-MRI allows for highly reliable assessment of acute intestinal GvHD and adds information indicating clinical severity., (© 2021. The Author(s).)

Rationale: PSMA-PET-CT enables measuring molecular expression of prostate-specific membrane antigen (PSMA) in vivo , which is the target molecule of 177 Lu-PSMA-617 (Lu-PSMA) therapy. However, the correlation of PSMA expression and overall survival (OS) in patients treated with Lu-PSMA therapy is currently unclear; especially with regard to coexistence of high and low PSMA expressing metastases. To this end, this retrospective single arm study elucidates the correlation of PSMA expression and overall survival in patients treated with Lu-PSMA therapy. Additionally, PET based criteria to define low PSMA expression were explored. Methods: Eighty-five patients referred to Lu-PSMA therapy were included in the analysis. Pretherapeutic 68 Ga-PSMA-PET-CT scans were available for all patients. SUV max of the highest PSMA expressing metastasis (PSMA max ), SUV max of the lowest PSMA expressing metastasis (PSMA min ), and average SUV max of all metastases (PSMA average ) amongst other PET parameters were measured for each patient. A log-rank cutoff-finder was used to determine low (lowPSMA average ) and high (highPSMA average ) average PSMA expression as well as low (lowPSMA min ) and high (highPSMA min ) minimal PSMA expression. Results: PSMA average was a significant prognosticator of overall survival in contrast to PSMA max (HR: 0.959; p = 0.047 vs. HR: 0.992; p = 0.231). Optimal log rank cut-offs were: PSMA average = 14.3; PSMA min = 10.2. Patients with low average PSMA expression (lowPSMA average ) had significantly shorter survival compared to those with high average expression (highPSMA average ) (5.3 vs. 15.1 months; p < 0.001; HR: 3.738, 95%CI = 1.953-7.154; p < 0.001). Patients with low PSMA expressing metastases (lowPSMA min ) had shorter survival compared to those without a low PSMA expressing metastasis (highPSMA min ) (p = 0.003; 7.9 months vs. 21.3; HR: 4.303, 95%CI = 1.521-12.178; p = 0.006). Patients that were classified as highPSMA average but with lowPSMA min had an intermediate overall survival (11.4 months; longer compared to lowPSMA average , 5.3 months, p = 0.002; but shorter compared to highPSMA min , 21.3 months, p = 0.02). Conclusion: Low average PSMA expression is a negative prognosticator of overall survival. Absence of low PSMA expressing metastases is associated with best overall survival and the maximum PSMA expression seems not suited to prognosticate overall survival. Low PSMA expression might therefore be a negative prognosticator for the outcome of patients treated with Lu-PSMA therapy. Future studies are warranted to elucidate the degree of low PSMA expression tolerable for Lu-PSMA therapy., (© The author(s).)

Background Fluorine 18 ( 18 F)-fluorodeoxyglucose (FDG) PET/CT is a routine tool for staging patients with lymphoma and lung cancer. Purpose To evaluate configurations of deep convolutional neural networks (CNNs) to localize and classify uptake patterns of whole-body 18 F-FDG PET/CT images in patients with lung cancer and lymphoma. Materials and Methods This was a retrospective analysis of consecutive patients with lung cancer or lymphoma referred to a single center from August 2011 to August 2013. Two nuclear medicine experts manually delineated foci with increased 18 F-FDG uptake, specified the anatomic location, and classified these findings as suspicious for tumor or metastasis or nonsuspicious. By using these expert readings as the reference standard, a CNN was developed to detect foci positive for 18 F-FDG uptake, predict the anatomic location, and determine the expert classification. Examinations were divided into independent training (60%), validation (20%), and test (20%) subsets. Results This study included 629 patients (mean age, 52.2 years ± 20.4 [standard deviation]; 394 men). There were 302 patients with lung cancer and 327 patients with lymphoma. For the test set (123 patients; 10 782 foci), the CNN areas under the receiver operating characteristic curve (AUCs) for determining hypermetabolic 18 F-FDG PET/CT foci that were suspicious for cancer versus nonsuspicious by using the five input features were as follows: CT alone, 0.78 (95% confidence interval [CI]: 0.72, 0.83); 18 F-FDG PET alone, 0.97 (95% CI: 0.97, 0.98); 18 F-FDG PET/CT, 0.98 (95% CI: 0.97, 0.99); 18 F-FDG PET/CT maximum intensity projection (MIP), 0.98 (95% CI: 0.98, 0.99); and 18 F-FDG PET/CT MIP atlas, 0.99 (95% CI: 0.98, 1.00). The combination of 18 F-FDG PET and CT information improved overall classification accuracy (AUC, 0.975 vs 0.981, respectively; P < .001). Anatomic localization accuracy of the CNN was 2543 of 2639 (96.4%; 95% CI: 95.5%, 97.1%) for body part, 2292 of 2639 (86.9%; 95% CI: 85.3%, 88.5%) for region (ie, organ), and 2149 of 2639 (81.4%; 95% CI: 79.3%-83.5%) for subregion. Conclusion The fully automated anatomic localization and classification of fluorine 18-fluorodeoxyglucose PET uptake patterns in foci suspicious and nonsuspicious for cancer in patients with lung cancer and lymphoma by using a convolutional neural network is feasible and achieves high diagnostic performance when both CT and PET images are used. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Froelich and Salavati in this issue.

The purpose of this study was to identify previous treatments and biomarker profile features that prognosticate overall survival (OS) in patients with mCRPC receiving 177 Lu-PSMA-617. Methods: 109 mCRPC patients treated with a median of 3 cycles of 177 Lu-PSMA-617 were included. Data were analyzed according to OS as well as PSA response patterns with regard to prior therapies, laboratory biomarkers and metastatic extent in univariate as well as multivariate Cox's proportional hazards models. PSA decline was assessed using the lowest PSA levels after the first cycle of therapy (initial PSA response) and during the entire observation period (best PSA response). Results: In total, 54 patients (49.5%) died during the observation period. First and second line chemotherapy were performed in 85% and 26%, and Abiraterone and Enzalutamide were administered in 83% and 85%, respectively. Any initial PSA decline occurred in 55% while 25% showed a PSA decline of ≥50%. The median estimated OS was 9.9 months (95% CI: 7.2-12.5) for all patients. Any initial decline of PSA was associated with significantly prolonged OS (15.5 vs. 5.7 months, p = 0.002). Second line cabazitaxel chemotherapy (6.7 vs. 15.7 months, p = 0.002) and presence of visceral metastases (5.9 vs. 16.4 months, p <0.001) were associated with shorter OS. Only visceral metastases remained significant in a multivariate analysis. Conclusion: 177 Lu-PSMA-617 is an effective therapy for patients with mCRPC. However, the present data indicate that its beneficial effects on OS are strongly influenced by pretreatment (history of second line chemotherapy with cabazitaxel) and the presence of visceral metastases at onset of 177 Lu-PSMA-617 treatment., Competing Interests: Competing Interests: The University of Münster received consulting fees from ABX GmbH, Radeberg, Germany for K.R. and M.B. Additionally K.R. is scientific consultant/ advisor of ABX GmbH. The authors declare they have no conflict of interest according to the subject and matter of the present article.

Background : Activation and dysregulation of innate, adaptive and resident immune cells in response to damage determine the pathophysiology of demyelinating disorders. Among the plethora of involved cells, microglia/macrophages and astrocytes play an important role in the pathogenesis of demyelinating disorders. The in-depth investigation of the spatio-temporal profile of these cell types in vivo may inform about the exact disease state and localization as well as may allow to monitor therapeutic modulation of the components of the neuroinflammatory response during the course of multiple sclerosis (MS). In this study, we aimed to non-invasively decipher the degree and temporal profile of neuroinflammation (TSPO - [ 18 F]DPA-714 PET) in relation to selected magnetic resonance imaging (MRI) parameters (T 2 maps) in the cuprizone (CPZ)-induced model of demyelination. Methods: C57Bl6 ( n=30 ) mice were fed with a standard chow mixed with 0.2% (w/w) CPZ for 4 ( n=10 ; demyelination) and 6 weeks ( n=10 ; spontaneous remyelination). The degree of neuroinflammation at de- and remyelination was assessed by [ 18 F]DPA-714 PET, multi-echo T 2 MRI, autoradiography and immunohistochemistry. Results : CPZ-induced brain alterations were confirmed by increase of T 2 relaxation times in both white and grey matter after 3 and 5 weeks of CPZ. Peak [ 18 F]DPA-714 was found in the corpus callosum (CC, white matter), the hippocampus (HC, grey matter) and thalamus (grey matter) after 4 weeks of CPZ treatment and declined after 6 weeks of CPZ. Ex vivo autoradiography and dedicated immunofluorescence showed demyelination/remyelination with corresponding increased/decreased TSPO levels in the CC and hippocampus, confirming the spatial distribution of [ 18 F]DPA-714 in vivo . The expression of TSPO microglia and astrocytes is time-dependent in this model. Microglia predominantly express TSPO at demyelination, while the majority of astrocytes express TSPO during remyelination. The combination of PET- and MRI-based imaging biomarkers demonstrated the regional and temporal development of the CPZ model-associated neuroinflammatory response in grey and white matter regions. Conclusions : The combination of [ 18 F]DPA-714 PET and T 2 mapping may allow to further elucidate the regional and temporal profile of inflammatory signals depending on the myelination status, although the underlying inflammatory microenvironment changes. A combination of the described imaging biomarkers may facilitate the development of patient-tailored strategies for immunomodulatory and neuro-restorative therapies in MS., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Diagnosis and localization of bacterial infections remains a significant clinical challenge. Harnessing bacteria-specific metabolic pathways, such as the maltodextrin transport mechanism, may allow specific localization and imaging of small or hidden colonies. This requires that the intrabacterial tracer accumulation provided by the transporter is matched by high serum stability of the tracer molecule. Herein, radiolabeled maltodextrins of varying chain lengths and with free nonreducing/reducing ends are reported and their behavior against starch-degrading enzymes in the blood, which compromise their serum stability, is evaluated. Successful single-photon emission computed tomography (SPECT) imaging is shown in a footpad infection model in vivo by using the newly developed model tracer, [ 99m Tc]MB1143, and the signal is compared with that of 18 F-fluorodeoxyglucose positron emission tomography ([ 18 F]FDG-PET) as a nonbacterial specific marker for inflammation. Although the [ 99m Tc]MB1143 imaging signal is highly specific, it is low, most probably due to insufficient serum stability of the tracer. A series of stability tests with different 18 F-labeled maltodextrins finally yielded clear structural guidelines regarding substitution patterns and chain lengths of maltodextrin-based tracers for nuclear imaging of bacterial infections., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The noninvasive imaging of MMP activity in vivo could have a high impact in basic research as well as in clinical applications. This approach can be established using radiolabeled MMP inhibitors (MMPIs) as tracers for the detection of activated MMPs by means of PET. However, the complexity of diseases associated with dysregulated MMP expression necessitates the imaging of distinct MMPs or MMP subgroups to distinguish their individual role in specific diseases. To this end, selective and potent MMP-13 inhibitors based on a N,N'-bis(benzyl)pyrimidine-4,6-dicarboxamide core have been synthesized and successfully radiolabeled with carbon-11, fluorine-18, and gallium-68. Selected radiolabeled candidates were evaluated in vitro and in vivo regarding their pharmacokinetic properties and metabolic stability.

Unlabelled: We evaluated the diagnostic value and accuracy of prostate-specific membrane antigen (PSMA) PET for the intraprostatic delineation of prostate cancer before prostatectomy., Methods: We identified 6 patients with biopsy-proven high-risk prostate cancer who were referred for (68)Ga-PSMA PET/CT before radical prostatectomy to rule out metastasis. After prostatectomy, a histologic map of the prostate was reconstructed. The histologic extent and Gleason score of each segment of the prostate were compared with (68)Ga-PSMA PET images resliced to the histologic axis. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated. The SUV of each segment was measured, and median values were compared., Results: Of the 132 segments, 112 were eligible for analysis. The correlation of histologic results with (68)Ga-PSMA PET images showed a specificity and sensitivity of 92%. The positive and negative likelihood ratio and the positive and negative predictive value for detection of prostate cancer on (68)Ga-PSMA PET were 11.5, 0.09, 96%, and 85%, respectively. The median SUVmax of true-positive prostate segments was significantly higher than that of true-negative segments (11.0 ± 7.8 vs. 2.7 ± 0.9, P< 0.001), and a cutoff of 4 revealed a sensitivity and specificity of 86.5% and an accuracy of 87.5%., Conclusion: These preliminary results show that the intraprostatic localization and extent of prostate cancer may be estimated by (68)Ga-PSMA PET. This imaging method may be helpful for identifying target lesions before prostate biopsy and may support decision making before focal or radical therapy., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Fluorine-containing inhibitors of matrix metalloproteinases (MMPs) can serve as lead structures for the development of (18)F-labeled radioligands. These compounds might be useful as non-invasive imaging probes to characterize pathologies associated with increased MMP activity. Results with a series of fluorinated analogs of a known biphenyl sulfonamide inhibitor have shown that fluorine can be incorporated into two different positions of the molecular scaffold without significant loss of potency in the nanomolar range. Additionally, the potential of a hitherto unknown fluorinated tertiary sulfonamide as MMP inhibitor has been demonstrated., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

N-Alkylated (S)-7-halogen-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins were developed as a new group of nonradioactive reference compounds for future radiotracers. Inhibitor potency studies of these compounds suggest that the binding pockets readily accommodate both the 7-halogen substituents and aliphatic side chains (methyl to n-butyl) as well as some ω-fluorinated analogues (3-fluoropropyl and 4-fluorobutyl) at the isatin nitrogen. Indeed, compared to the halogen free parent compounds, some 7-halogenated derivatives exhibited slightly improved inhibitory potencies with IC50 values up to 2.6 nM (caspase-3) and 3.3 nM (caspase-7), respectively. Moreover, the 7-position of isatin, a potential cytochrome P450 hydroxylation site, was substituted by I, Br, Cl, and F to potentially enhance the metabolic stability of isatin sulfonamides. As an example, the radiotracer [(18)F]39 that was produced by (19)F/(18)F isotope exchange was shown to be stable in human blood serum after incubation at 37 °C for at least 90 min.

Sphingosine-1-phosphate (S1P) receptors play major roles in cardiovascular, immunological and neurological diseases. The recent approval of the sphingolipid drug Fingolimod (Gilenya®), a sphingosine-1-phosphate agonist for relapsing multiple sclerosis, in 2010 exemplifies the potential for targeting sphingolipids for the treatment of human disorders. Moreover, non-invasive in vivo imaging of S1P receptors that are not available till now would contribute to the understanding of their role in specific pathologies and is therefore of preclinical interest. Based on fluorinated analogues of the S1P1 receptor antagonist W146 showing practically equal in vitro potency as the lead structure, the first S1P receptor antagonist [18F]-radiotracer has been synthesized and tested for in vivo imaging of the S1P1 receptor using positron emission tomography (PET). Though the tracer is serum stable, initial in vivo images show fast metabolism and subsequent accumulation of free [18F]fluoride in the bones., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The effector caspases-3 and -7 play a central role in programmed type I cell death (apoptosis). Molecular imaging using positron emission tomography (PET) by tracking the activity of executing caspases might allow the detection of the early onset as well as therapy monitoring of various diseases induced by dysregulated apoptosis. Herein, four new fluorinated diastereo- and enantiopure isatin sulfonamide-based potent and selective caspase-3 and -7 inhibitors were prepared by cyclic sulfate ring-opening with fluoride. All fluorohydrins exhibited excellent in vitro affinities (up to IC50 = 11.8 and 0.951 nM for caspase-3 and -7, respectively), which makes them appropriate PET radiotracer candidates. Therefore, N-(4-[(18)F]fluoro-3(R)-hydroxybutyl)- and N-(3(S)-[(18)F]fluoro-4-hydroxybutyl)-5-[1-(2(S)-(methoxymethyl)pyrrolidinyl)sulfonyl]isatin were synthesized in 140 min with 24% and 10% overall radiochemical yields and specific activities of 10-127 GBq/μmol using [(18)F]fluoride in the presence of Kryptofix and subsequent acidic hydrolysis. In vivo biodistribution studies in wild-type mice using PET/computed tomography imaging proved fast clearance of the tracer after tail vein injection.

The number of patients with end-stage renal disease, and the number of kidney allograft recipients continuously increases. Episodes of acute cellular allograft rejection (AR) are a negative prognostic factor for long-term allograft survival, and its timely diagnosis is crucial for allograft function (1). At present, AR can only be definitely diagnosed by core-needle biopsy, which, as an invasive method, bares significant risk of graft injury or even loss. Moreover, biopsies are not feasible in patients taking anticoagulant drugs and the limited sampling site of this technique may result in false negative results if the AR is focal or patchy. As a consequence, this gave rise to an ongoing search for new AR detection methods, which often has to be done in animals including the use of various transplantation models. Since the early 60s rat renal transplantation is a well-established experimental method for the examination and analysis of AR (2). We herein present in addition small animal positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) to assess AR in an allogeneic uninephrectomized rat renal transplantation model and propose graft FDG-PET imaging as a new option for a non-invasive, specific and early diagnosis of AR also for the human situation (3). Further, this method can be applied for follow-up to improve monitoring of transplant rejection (4).

Unlabelled: In the diagnostic algorithm of cardiac tumors, the noninvasive determination of malignancy and metastatic spread is of major interest to stratify patients and to select and monitor therapies. In the diagnostic work-up, morphologic imaging modalities such as echocardiography or magnetic resonance tomography offer information on, for example, size, invasiveness, and vascularization. However, preoperative assessment of malignancy may be unsatisfactory. The aim of this study was to evaluate the diagnostic value of (18)F-FDG PET and the incremental diagnostic value of an optimized CT score in this clinical scenario., Methods: (18)F-FDG PET/CT scans (whole-body imaging with low-dose CT) of 24 consecutive patients with newly diagnosed cardiac tumors were analyzed (11 men, 13 women; mean age ± SD, 59 ± 13 y). The maximum standardized uptake values (SUV(max)) of the tumors were measured. Patients were divided into 2 groups: benign cardiac tumors (n = 7) and malignant cardiac tumors (n = 17) (cardiac primaries [n = 8] and metastases [n = 9]). SUV(max) was compared between the 2 groups. Results were compared with contrast-enhanced CT, using standardized criteria of malignancy. Histology served as ground truth., Results: Mean SUV(max) was 2.8 ± 0.6 in benign cardiac tumors and significantly higher both in malignant primary and in secondary cardiac tumors (8.0 ± 2.1 and 10.8 ± 4.9, P < 0.01). Malignancy was determined with a sensitivity of 100% and specificity of 86% (accuracy, 96%), after a cutoff with high sensitivity (SUV(max) of 3.5) was chosen to avoid false-negatives. Morphologic imaging reached a sensitivity of 82% and a specificity of 86% (accuracy, 83%). Both false-positive and false-negative decisions in morphology could be corrected in all but 1 case using a metabolic threshold with an SUV(max) of 3.5. In addition, extracardiac tumor manifestations were detected in 4 patients by whole-body (18)F-FDG PET/CT., Conclusion: (18)F-FDG PET/CT can aid the noninvasive preoperative determination of malignancy and may be helpful in detecting metastases of malignant cardiac tumors.

Acute ruptures of atherosclerotic plaques with subsequent occlusion account for the vast majority of clinical events such as myocardial infarction or stroke. New imaging approaches focusing on the visualization of inflammation in the vessel wall could emerge as tools for individualized risk assessment and prevention of events. To this end, PET employing (18)F-fluorodeoxyglucose (FDG) has recently been introduced for the first clinical trials. Although this approach nicely visualizes plaques inflammation questions remain with respect to if and how this inflammatory signal can be employed for predicting individual plaque rupture. Molecular imaging of proteases such as matrix-metalloproteinases (MMPs) involved in several steps in plaque progression driving plaques into vulnerable, rupture-prone states seems a promising alternative approach. This review introduces and discusses the vulnerable plaque concept, animal models with human-like plaque ruptures and the potential of a FDG versus a non-FDG MMP-targeted strategy to image rupture-prone plaques.

In vivo imaging of MMPs is of great (pre)clinical interest and can potentially be realized with modern three-dimensional and noninvasive in vivo molecular imaging techniques such as positron emission tomography (PET). Consequently, MMP inhibitors (MMPIs) radiolabeled with positron emitting nuclides (e.g., (18)F) represent a suitable tool for the visualization of activated MMPs with PET. On the basis of our previous work and results regarding radiolabeled and unlabeled derivatives of the nonselective MMPIs, we discovered a new class of fluorinated MMPIs with a triazole-substituted hydroxamate substructure. These novel MMPIs are characterized by an increased hydrophilicity compared with the lead structures and excellent MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13 (IC(50) = 0.006-107 nM). Therefore, one promising fluorinated triazole-substituted hydroxamate (30b) was selected and resynthesised as its (18)F-labeled version to yield the potential PET radioligand [(18)F]30b. The biodistribution behavior of this novel compound was investigated with small animal PET.

Radiolabeled C-5-disubstituted pyrimidine-2,4,6-triones have recently been suggested by our group as a class of potent matrix metalloproteinase (MMP) targeted radiotracers that can noninvasively visualize activated MMPs by means of positron emission tomography (PET). MMPs belong to the zinc- and calcium-dependent endopeptidases which are involved in the proteolytic degradation of components of the extracellular matrix (ECM) but also are capable of processing and releasing bioactive molecules such as growth factors, proteinase inhibitors, and cytokines. Locally increased levels of activated MMPs modulate and contribute to the progression of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific and noninvasive visualization of aforementioned pathologies in vivo. On the basis of our recent results, we here describe a series of new fluorinated pyrimidine-2,4,6-triones of the second generation with maintained MMP inhibition potencies (IC(50) = 4-605 nM), which are fine-tuned toward more hydrophilic versions, and show the improved biodistribution behavior of one selected radiofluorinated pyrimidine-2,4,6-trione by means of small-animal PET.

The expression and function of endothelin (ET) receptors are abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. A previously reported promising radioligand for positron emission tomography (PET) based on the non-peptide ET(A) receptor antagonist PD 156707 showed specific binding to target receptors in the myocardium but high accumulation in bile and intestine, probably because of its high lipophilicity. In this study we describe the synthesis of a series of fluorinated derivatives with hydrophilic building blocks. All compounds were evaluated as high affinity ET(A) receptor ligands (16, 17, 23-26, K(i) = 1.4-7.9 nM) with high subtype selectivity over the ET(B) receptor. [(18)F]3-Benzo[1,3]dioxol-5-yl-4-{3-[1-(2-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}ethyl)-1H-[1,2,3]triazol-4-ylmethoxy]-4,5-dimethoxybenzyl}-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one ([(18)F]17) was synthesized as one of the radioligands of this series that possesses a higher hydrophilicity and an excellent stability in human serum. Improved clearance properties and specific uptake in target organs have been confirmed by biodistribution studies and small animal PET imaging.

Unlabelled: Dysfunction of the sympathetic nervous system underlies many cardiac diseases and can be assessed by molecular imaging using PET in humans. Small-animal PET should enable noninvasive quantitation of the sympathetic nervous system in mouse models of human disease. For mice, however, the radioactivity needed to give acceptable image quality may be associated with a mass of unlabeled compound sufficient to block the binding of radioligand to its target. The present study assesses the feasibility of using [N-methyl-(11)C]meta-hydroxyephedrine ((11)C-mHED) to measure norepinephrine reuptake in humans, to determine cardiac innervation in mice., Methods: Anesthetized mice were placed in a small-animal PET scanner. (11)C-mHED (containing 18% precursor metaraminol) was injected via a tail vein into each animal simultaneously. Fifteen minutes later, animals were injected with saline or metaraminol which competes with mHED for norepinephrine reuptake. (18)F-FDG was injected at 60 min to identify heart regions. After reconstruction of the list-mode data, radioactivity in myocardial regions was computed using in-house software, and time-activity curves were plotted., Results: Hearts were clearly visualized after injection of (11)C-mHED. Injection of metaraminol at doses less than 50 nmol x kg(-1) had no effect, whereas doses greater than 100 nmol x kg(-1) caused a dose-dependent loss of specifically bound radioactivity., Conclusion: (11)C-mHED was successfully used to visualize and assess myocardial innervation in mice. Uptake of (11)C-mHED is displaceable by the false transmitter metaraminol. The total molar dose of metaraminol and (11)C-mHED must be considered in the analysis of PET data.

Purpose: Inflamed atherosclerotic plaques may rupture and cause acute myocardial infarction, stroke and other thrombotic events. Early detection of these unstable plaques could, in many cases, prevent such potentially fatal events. 11C-choline or 18F-labelled choline derivatives for visualizing the synthesis of phospholipids, are promising markers of plaque inflammation with potential advantages over 18F-FDG. Their potential for plaque characterization in humans is, however, unclear. In this study the prevalence and distribution of 11C-choline uptake in the aortic and common carotid arterial walls of elderly male patients was evaluated with combined PET/CT. Additionally, the localization of radiotracer uptake and calcification was correlated in various vessel segments., Methods: Image data from 93 consecutive male patients between 60 and 80 years old who had undergone whole-body 11C-choline PET/CT assessment for prostate cancer were evaluated retrospectively. 11C-choline uptake and calcification were analysed qualitatively and semiquantitatively and compared., Results: 11C-choline uptake was found in 95% of patients, calcification in 94% throughout all vessel segments. In 6% of the patients radiotracer uptake was colocalized with calcifications, whereas less than 1% of calcification sites showed increased radiotracer uptake., Conclusion: Both 11C-choline uptake and calcification in the aortic and common carotid arterial walls are common in elderly men. Radiotracer uptake and calcification are, however, only rarely colocalized. 11C-choline has the potential to provide information about atherosclerotic plaques independent of calcification measurement.

Unlabelled: Recent studies have shown that idiopathic atrial fibrillation (AF) is associated with diminished myocardial perfusion and perfusion reserve, which are also impaired in various forms of cardiomyopathies. In many cases, AF develops during progression of dilated cardiomyopathy (DCM) and may aggravate heart failure. This study compared myocardial perfusion between patients with nonischemic DCM with and without AF., Methods: Twelve men (age +/- SD, 55 +/- 12 y) who had DCM and persistent AF were compared with a group of 18 men (mean age, 43 +/- 15 y, P = not statistically significant) who had DCM and sinus rhythm and with 22 healthy controls (mean age, 47 +/- 13 y, P = not statistically significant). Myocardial blood flow (MBF) was noninvasively quantified at rest and during adenosine infusion using PET and radioactive-labeled water (H(2)(15)O PET)., Results: Compared with controls, DCM patients without AF showed impaired hyperemic perfusion (2.52 +/- 1.29 vs. 3.57 +/- 0.88 mL/min/mL, P = 0.014) and perfusion reserve (2.10 +/- 1.01 vs. 3.37 +/- 0.97, P = 0.003). However, compared with DCM patients without AF, DCM patients with AF showed an additional impairment in resting perfusion (0.82 +/- 0.31 mL/min/mL, P = 0.010) and hyperemic perfusion (1.32 +/- 0.93 mL/min/mL, P = 0.022), and compared with controls, DCM patients with AF showed a further diminishment of perfusion reserve (1.68 +/- 0.94 vs. 3.37 +/- 0.97, P < 0.001) accompanied by the highest coronary vascular resistance of all groups., Conclusion: Compared with patients with sinus rhythm, patients with AF have significantly reduced myocardial perfusion reserve and increased coronary resistance in nonischemic DCM. Further studies on the underlying pathomechanisms are warranted.

An approach to the in vivo imaging of locally upregulated and activated matrix metalloproteinases (MMPs) found in many pathological processes is offered by positron emission tomography (PET). Hence, appropriate PET radioligands for MMP imaging are required. Here, we describe the syntheses of novel fluorinated MMP inhibitors (MMPIs) based on lead structures of the broad-spectrum inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)-amino]-3-methyl-butanamide (CGS 25966) and N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](3-picolyl)-amino]-3-methyl-butanamide (CGS 27023A). Additionally, tailor-made precursor compounds for radiolabeling with the positron-emitter 18F were synthesized. All prepared hydroxamate target compounds showed high in vitro MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13. As a consequence, the promising fluorinated hydroxamic acid derivative 1f was resynthesized in its 18F-labeled version via two different procedures yielding the potential PET radioligand [18F]1f. As expected, the biodistribution behavior of this novel compound and that of the more hydrophilic variant [18F]1j, also developed by our group, indicates that there was no tissue specific accumulation in wild-type (WT) mice.

Molecular cardiovascular imaging plays an increasingly important role both in basic research and in clinical diagnosis. Scintigraphic methods have long been used to study pathophysiological changes on a cellular and molecular level, and they are likely to remain important molecular imaging modalities in the foreseeable future. This article provides an overview over current developments in cardiovascular molecular imaging using scintigraphic methods. The focus lies on imaging of cardiac innervation, plaque instability, hypoxia and angiogenesis, gene expression and stem and progenitor cell migration and proliferation.

Introduction: Inflammation plays an important role in vulnerability of atherosclerotic plaques to rupture and hence acute coronary events. The monocyte-macrophage infiltration in plaques leads to upregulation of cytokines and metalloproteinase enzymes. Matrix metalloproteinases result in matrix dissolution and consequently expansive remodeling of the vessel. They also contribute to attenuation of fibrous cap and hence susceptibility to rupture. Assessment of metalloproteinase expression and activity should provide information about plaque instability.

Purpose: The segmentation algorithm ESM based on an elastic surface model was validated for the assessment of left ventricular volumes and ejection fraction from ECG-gated myocardial perfusion SPECT. Additionally, it was compared with the commercially available quantification packages 4D-MSPECT and QGS. Cardiac MRI was used as the reference method., Methods: SPECT and MRI were performed on 70 consecutive patients with suspected or proven coronary artery disease. End-diastolic (EDV) and end-systolic (ESV) volumes and left ventricular ejection fraction (LVEF) were derived from SPECT studies by using the segmentation algorithms ESM, 4D-MSPECT and QGS and from cardiac MRI., Results: ESM-derived values for EDV and ESV correlated well with those from cardiac MRI (correlation coefficients R=0.90 and R=0.95, respectively), as did the measurements for LVEF (R=0.86). Both EDV and ESV were slightly overestimated for larger ventricles but not for smaller ventricles; LVEF was slightly overestimated irrespective of ventricle size. The above correlation coefficients are comparable to those for the 4D-MSPECT and QGS segmentation algorithms. However, results obtained with the three segmentation algorithms are not interchangeable., Conclusion: The ESM algorithm can be used to assess EDV, ESV and LVEF from gated perfusion SPECT images. Overall, the performance was similar to that of 4D-MSPECT and QGS when compared with cardiac MRI. Results obtained with the three tested segmentation methods are not interchangeable, so that the same algorithm should be used for follow-up studies and control subjects.

Studies have demonstrated a positive correlation between inflammation, metastasis, or atherosclerosis and the unbalanced or culminated expression of matrix metalloproteinases (MMPs). The molecular imaging of locally upregulated MMP activity in vivo is a clinical challenge. Actually, radioligands based on nonpeptidyl MMP inhibitors (MMPIs) are currently in development as putative radiopharmaceutical agents for the noninvasive in vivo assessment of activated MMPs. Nonpeptidyl MMPIs bind to the zinc active site of the activated enzyme via mono- (e.g. carboxylate) or bidentate (e.g. hydroxamate) complexation thereby exhibiting a broad-spectrum MMP binding potency. Thus, these mentioned endopeptidase inhibitors should be useable lead compounds for the redevelopment as diagnostic MMPI radiotracers. Recently, the non-hydroxamate C-5-disubstituted pyrimidine-2,4,6-triones were disclosed as subgroup-selective MMP inhibitors. We here describe a set of fine-tuned barbiturates as a new class of MMPI radiotracers for the noninvasive in vivo visualization of activated MMPs using scintigraphic techniques such as SPECT or PET.

Simple Summary: Biomarkers reliably predicting treatment response to immune checkpoint inhibition (CKI) therapy in advanced non-small cell lung cancer (NSCLC) are warranted. Baseline 18F-FDG-PET-CT (PET-CT) is an integral part of the diagnostic algorithm of NSCLC. However, there is poor evidence on the predictive and prognostic value of initial PET-CT imaging in these patients. The use of Radiomics has gained prominence in the last decade allowing for the extraction and artificial intelligence-based analysis of additional imaging parameters, so-called radiomic features (RFs). We aimed to find RFs predicting treatment response for CKI-based first-line therapy in advanced NSCLC patients, out of whole-body metabolic PET and morphological CT imaging. PET RFs might additionally be predictive and prognostic and could thus provide important information for future therapy monitoring and guidance. We aimed to evaluate the predictive and prognostic value of baseline 18F-FDG-PET-CT (PET-CT) radiomic features (RFs) for immune checkpoint-inhibitor (CKI)-based first-line therapy in advanced non-small-cell lung cancer (NSCLC) patients. In this retrospective study 44 patients were included. Patients were treated with either CKI-monotherapy or combined CKI-based immunotherapy–chemotherapy as first-line treatment. Treatment response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). After a median follow-up of 6.4 months patients were stratified into "responder" (n = 33) and "non-responder" (n = 11). RFs were extracted from baseline PET and CT data after segmenting PET-positive tumor volume of all lesions. A Radiomics-based model was developed based on a Radiomics signature consisting of reliable RFs that allow classification of response and overall progression using multivariate logistic regression. These RF were additionally tested for their prognostic value in all patients by applying a model-derived threshold. Two independent PET-based RFs differentiated well between responders and non-responders. For predicting response, the area under the curve (AUC) was 0.69 for "PET-Skewness" and 0.75 predicting overall progression for "PET-Median". In terms of progression-free survival analysis, patients with a lower value of PET-Skewness (threshold < 0.2014; hazard ratio (HR) 0.17, 95% CI 0.06–0.46; p < 0.001) and higher value of PET-Median (threshold > 0.5233; HR 0.23, 95% CI 0.11–0.49; p < 0.001) had a significantly lower probability of disease progression or death. Our Radiomics-based model might be able to predict response in advanced NSCLC patients treated with CKI-based first-line therapy. [ABSTRACT FROM AUTHOR]

Many serious diseases such as cancer, atherosclerosis and arthritis are characterized by upregulation of activated matrix metalloproteinases (MMPs). For this reason imaging and quantification of activated MMPs with the molecular imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) using radiolabeled MMP inhibitors would be a valuable tool for the diagnosis and therapy planning of mentioned diseases. This work aims at the synthesis and preliminary in vitro and in vivo evaluation of positron‐emitter 18F‐fluorine labeled radiotracers based on 2‐{[(4‐phenoxyphenyl)sulfonyl]methyl}thiirane (SB‐3CT), a slow‐binding and mechanism‐based MMP‐2 and −9 inhibitor. Therefore, a library of fluorinated SB‐3CT derivatives were prepared and evaluated in vitro in MMP inhibition assays. From this pool the 18F‐labeled triazole [18F]18d was successfully synthesized in a two‐step procedure. However, this compound was unstable in human and mouse serum and showed a biodistribution behavior in C57BL/6 mice that is not favorable for PET imaging preventing further in vivo evaluations in MMP‐associated mouse models of disease. Imaging of matrix metalloproteinases (MMPs) dysregulated in a multitude of diseases with positron emission tomography (PET) is of great clinical interest. For the first time the thiirane‐based SB‐3CT, exhibiting the unique characteristic of slow‐binding inhibition of MMP‐2 and −9, served as lead structure for 18F‐labeled radiotracer development. The first representative of this compound class ([18F]18d) was evaluated in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a single compound allowing visualization and therapy simultaneously, the concept has been widened with the development of theranostic pairs and the combination of nuclear medicine with different types of cancer therapies. Here, we review the clinical applications of different theranostic radiopharmaceuticals in managing different tumor types (differentiated thyroid, neuroendocrine prostate, and breast cancer) that support the combination of innovative oncological therapies such as gene and cell-based therapies with RT. [ABSTRACT FROM AUTHOR]