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In an effort to seek novel agents targeting prostate-specific membrane antigen (PSMA), 16 ligands ( L1 - L16 ) with structural modifications in S1' binding pocket were synthesized and evaluated for PSMA inhibition. ( S )-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido)propanoic acids proved to be potent PSMA ligands with K i values ranging from 0.08 nM to 8.98 nM, which are in the range of or are higher in potency compared to previously published urea-based ligands. Computational docking was performed to study the binding mode of the two most potent ligands discovered. FITC-conjugated L14 could selectively stain PSMA + LNCaP cells over PSMA - PC3 cells. IRDye800CW conjugated L16 can effectively image tumors in a murine xenograft model of prostate cancer.

Competing Interests: Conflicts of Interest: MG Pomper is a co-inventor on a US patent covering 18F-DCFPyL and as such is entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. MA Gorin has served as a consultant for Progenics Pharmaceuticals Inc., the licensee of 18F-DCFPyL. SP Rowe is a consultant for Progenics Pharmaceuticals Inc.

Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine the effect of β- and γ-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the β- and γ-amino acid analogues with ( S )- or ( R )-configuration with keeping α-(l)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound 13c , a β-amino acid analogue with ( R )-configuration, exhibited the most potent PSMA inhibitory activity with an IC 50 value of 3.97 nM. The X-ray crystal structure of PSMA in complex with 13c provided a mechanistic basis for the stereochemical preference of PSMA, which can guide the development of future PSMA inhibitors.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is involved in several cognitive and physiologic processes; its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer's disease, which makes it a relevant drug target. Development of selective radioligands is important for defining binding properties and occupancy of novel molecules targeting the receptor. We tested the in vitro binding properties of [ 125 I]Iodo-ASEM [(3-(1,4-diazabycyclo[3.2.2]nonan-4-yl)-6-( 125 I-iododibenzo[b,d]thiopentene 5,5-dioxide)] in the mouse, rat and pig brain using autoradiography. The in vivo binding properties of [ 18 F]ASEM were investigated using positron emission tomography (PET) in the pig brain. [ 125 I]Iodo-ASEM showed specific and displaceable high affinity (~1 nM) binding in mouse, rat, and pig brain. Binding pattern overlapped with [ 125 I]α-bungarotoxin, specific binding was absent in α7 nAChR gene-deficient mice and binding was blocked by a range of α7 nAChR orthosteric modulators in an affinity-dependent order in the pig brain. Interestingly, relative to the wild-type, binding in β2 nAChR gene-deficient mice was lower for [ 125 I]Iodo-ASEM (58% ± 2.7%) than [ 125 I]α-bungarotoxin (23% ± 0.2%), potentially indicating different binding properties to heteromeric α7β2 nAChR. [ 18 F]ASEM PET in the pig showed high brain uptake and reversible tracer kinetics with a similar spatial distribution as previously reported for α7 nAChR. Blocking with SSR-180,711 resulted in a significant decrease in [ 18 F]ASEM binding. Our findings indicate that [ 125 I]Iodo-ASEM allows sensitive and selective imaging of α7 nAChR in vitro, with better signal-to-noise ratio than previous tracers. Preliminary data of [ 18 F]ASEM in the pig brain demonstrated principal suitable kinetic properties for in vivo quantification of α7 nAChR, comparable to previously published data.

Objective: The primary objective of this preliminary study was to examine the impact of NFL play on interregional functional connectivity between two brain regions, the supramarginal gyrus (SMG) and the thalamus, identified as having higher binding of [ 11 C]DPA-713 in NFL players. The authors' secondary objective was to examine the effect of years since play on the interregional connectivity., Methods: Resting-state functional MRI was used to examine functional brain changes between regions with evidence of past injury in active or recently retired NFL players (defined as ≤12 years since NFL play) and distantly retired players (defined as >12 years since NFL play). Age-comparable individuals without a history of concussion or participation in collegiate or professional collision sports were included as a control group., Results: Compared with healthy control subjects, NFL players showed a loss of anticorrelation between the left SMG and bilateral thalami (mean z score=-2.434, p=0.015). No difference was observed when examining right SMG connectivity. The pattern of connectivity in active and recently retired players mimicked the pattern observed in distantly retired players and older control subjects., Conclusions: Further study of the clinical significance of this altered pattern of interregional connectivity in active and recently retired NFL players is needed.

Nuclear medicine is experiencing a renaissance, with U.S. Food and Drug Administration approval recently being obtained for theranostic agents and a wide variety of such agents soon to impact patient care significantly in the era of precision medicine. The NETTER-1 trial demonstrated the therapeutic effect of a theranostic agent in markedly improving progression-free survival in patients with metastatic gastroenteropancreatic neuroendocrine tumors. Predominantly retrospective studies have demonstrated a significant response to 177 Lu-labeled agents targeting prostate-specific membrane antigen (PSMA) in patients with prostate cancer. At least 2 prospective clinical trials involving 177 Lu-PSMA agents are under way that will likely pave the way for Food and Drug Administration approval in the United States. A significant upside to theranostics is that patients tend to tolerate these agents better than chemotherapy. Theranostic compounds are likely to impact many cancers in the near future, not only through improvements in quality of life but also in terms of survival. This article provides an overview of already approved agents as well as those on the horizon. It is important that as these agents are clinically onboarded, nuclear medicine physicians have the expertise to deploy theranostics safely and efficiently, ensuring that these agents attain and maintain their position as leading lines of therapy in managing patients with cancer as well as becoming an important aspect of nuclear medicine practice in the future., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Emerging evidence supports a hypothesized role for the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease. 18 F-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6- 18 F-fluorodibenzo[b,d]thiophene 5,5-dioxide) is a radioligand for estimating the availability of α7-nAChR in the brain in vivo with PET. Methods: In this cross-sectional study, 14 patients with mild cognitive impairment (MCI), a prodromal stage to dementia, and 17 cognitively intact, elderly controls completed 18 F-ASEM PET. For each participant, binding in each region of interest was estimated using Logan graphical analysis with a metabolite-corrected arterial input function. Results: Higher 18 F-ASEM binding was observed in MCI patients than in controls across all regions, supporting higher availability of α7-nAChR in MCI. 18 F-ASEM binding was not associated with verbal memory in this small MCI sample. Conclusion: These data support use of 18 F-ASEM PET to examine further the relationship between α7-nAChR availability and MCI., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Auger radiopharmaceutical therapy is a promising strategy for micrometastatic disease given high linear energy transfer and short range in tissues, potentially limiting normal tissue toxicities. We previously demonstrated anti-tumor efficacy of a small-molecule Auger electron emitter targeting the prostate-specific membrane antigen (PSMA), 2-[3-[1-carboxy-5-(4-[ 125 I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid), or 125 I-DCIBzL, in a mouse xenograft model. Here, we investigated the therapeutic efficacy, long-term toxicity, and biodistribution of 125 I-DCIBzL in a micrometastatic model of prostate cancer (PC). Methods : To test the therapeutic efficacy of 125 I-DCIBzL in micrometastatic PC, we used a murine model of human metastatic PC in which PSMA+ PC3-ML cells expressing firefly luciferase were injected intravenously in NSG mice to form micrometastatic deposits. One week later, 0, 0.37, 1.85, 3.7, 18.5, 37, or 111 MBq of 125 I-DCIBzL was administered (intravenously). Metastatic tumor burden was assessed using bioluminescence imaging (BLI). Long-term toxicity was evaluated via serial weights and urinalysis of non-tumor-bearing mice over a 12-month period, as well as final necropsy. Results : In the micrometastatic PC model, activities of 18.5 MBq 125 I-DCIBzL and above significantly delayed development of detectable metastatic disease by BLI and prolonged survival in mice. Gross metastases were detectable in control mice and those treated with 0.37-3.7 MBq 125 I-DCIBzL at a median of 2 weeks post-treatment, versus 4 weeks for those treated with 18.5-111 MBq 125 I-DCIBzL ( P <0.0001 by log-rank test). Similarly, treatment with ≥18.5 MBq 125 I-DCIBzL yielded a median survival of 11 weeks, compared with 6 weeks for control mice ( P <0.0001). At 12 months, there was no appreciable toxicity via weight, urinalysis, or necropsy evaluation in mice treated with any activity of 125 I-DCIBzL, which represents markedly less toxicity than the analogous PSMA-targeted α-particle emitter. Macro-to-microscale dosimetry modeling demonstrated lower absorbed dose in renal cell nuclei versus tumor cell nuclei due to lower levels of drug uptake and cellular internalization in combination with the short range of Auger emissions. Conclusion : PSMA-targeted radiopharmaceutical therapy with the Auger emitter 125 I-DCIBzL significantly delayed development of detectable metastatic disease and improved survival in a micrometastatic model of PC, with no long-term toxicities noted at 12 months, suggesting a favorable therapeutic ratio for treatment of micrometastatic PC., Competing Interests: Competing Interests: Dr. Kiess has received clinical research funding from Advanced Accelerator Applications/Novartis. No other potential conflict of interest relevant to this article was reported., (© The author(s).)

Purpose: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging has impacted the management of patients with prostate cancer (PCa) in many parts of the world. PSMA-targeted endoradiotherapies are also being increasingly utilized and for these applications, the radiopharmaceutical distribution in normal organs is particularly important because it may limit the dose that can be delivered to tumors. In this study, we measured both interpatient and intrapatient variability of [ 18 F]DCFPyL uptake in the most relevant normal organs., Procedures: Baseline and 6-month follow-up PSMA-targeted [ 18 F]DCFPyL PET/computed tomography (CT) scans from 39 patients with PCa were reviewed. Volumes of interest were manually drawn using the best visual approximation of the organ edge for both lacrimal glands, all four major salivary glands, the liver, the spleen, and both kidneys for all patients. The average SUV mean , the COVs, and intraclass correlation coefficients (ICCs) across scans were calculated. Bland-Altman analyses were performed for all organs to derive repeatability coefficients (RCs)., Results: The liver demonstrated the lowest interpatient variability (13.0 and 16.6 % at baseline and follow-up, respectively), while the spleen demonstrated the largest interpatient variability (44.6 and 51.0 % at baseline and follow-up, respectively). The lowest intrapatient variability was found in the spleen (ICC 0.86) while the highest intrapatient variability was in the kidneys (ICCs 0.40-0.50). Bland-Altman analyses showed 95 % repeatability coefficients for mean uptake > 40 % for multiple organs and were highest for the lacrimal glands, kidneys, and spleen., Conclusions: Normal organs demonstrate significant variability in uptake of the PSMA-targeted radiotracer [ 18 F]DCFPyL. Depending on the organ, different contributions of interpatient and intrapatient factors affect the intrinsic variability. The RCs also vary significantly among the different organs were highest for the lacrimal glands, kidneys, and spleen. These findings may have important implications for the design of clinical protocols and personalized dosimetry for PSMA-targeted endoradiotherapies.

Bone metastases in prostate cancer (PCa) have important prognostic significance, and imaging modalities used for PCa staging should have high sensitivity for detecting such lesions. Prostate-specific membrane antigen (PSMA)-targeted PET radiotracers are promising new agents for imaging PCa. We undertook a head-to-head comparison of PSMA-targeted 2-(3-{1-carboxy-5-[(6- 18 F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ( 18 F-DCFPyL) PET to Na 18 F PET to determine which modality was more sensitive for the detection of lesions suggestive of bone metastases in a group of patients with metastatic PCa. Methods: Patients with progressive, metastatic PCa were prospectively imaged with both 18 F-DCFPyL and Na 18 F PET/CT, with both scans occurring within 24 h of each other. A consensus 2-reader central review was performed to identify all bone lesions suggestive of sites of PCa involvement on both scans, and maximized SUVs corrected for body weight (SUV max ) and lean body mass (SUL max ) were recorded. Soft-tissue lesions were also noted on both scans, and SUV max , SUL max , and PSMA reporting and data system (RADS) version 1.0 scores were recorded. Data from the 2 scans were compared using a generalized estimating equation. Results: In total, 16 patients meeting all inclusion criteria were enrolled in this study, and 15 of the 16 (93.8%) were imaged with both PET radiotracers. In total, 405 bone lesions suggestive of sites of PCa were identified on at least 1 scan. On 18 F-DCFPyL PET/CT, 391 (96.5%) were definitively positive, 4 (1.0%) were equivocally positive, and 10 (2.5%) were negative. On Na 18 F PET/CT, the corresponding values were 388 (95.8%), 4 (1.0%), and 13 (3.2%). Of the definitively negative lesions on 18 F-DCFPyL PET, 8 of 10 (80.0%) were sclerotic and 2 of 10 (20.0%) were infiltrative or marrow-based. Additionally, 12 of 13 (92.3%) of the definitively negative lesions on Na 18 F PET were infiltrative or marrow-based and 1 of 13 (7.7%) was lytic. Also identified were 78 PSMA-RADS-4, 17 PSMA-RADS-5, and 1 PSMA-RADS-3C soft-tissue lesions. Conclusion: PET/CT imaging using 18 F-DCFPyL and Na 18 F PET had nearly identical sensitivities for the detection of bone lesions in patients with metastatic PCa. As would be expected, PSMA-targeted PET provides more information on soft-tissue disease. There may be little additional value to imaging PCa patients with Na 18 F after a PSMA-targeted PET scan has already been performed., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: In this study, we aimed to quantitatively investigate the biodistribution of [ 18 F]DCFPyL in patients with prostate cancer (PCa) and to determine whether uptake in normal organs correlates with an increase in tumor burden., Procedures: Fifty patients who had been imaged with [ 18 F]DCFPyL positron emission tomography/computed tomography (PET/CT) were retrospectively included in this study. Forty of 50 (80 %) demonstrated radiotracer uptake on [ 18 F]DCFPyL PET/CT compatible with sites of PCa. Volumes of interests (VOIs) were set on normal organs (lacrimal glands, parotid glands, submandibular glands, liver, spleen, and kidneys) and on tumor lesions. Mean standardized uptake values corrected to lean body mass (SUL mean ) and mean standardized uptake values corrected to body weight (SUV mean ) for normal organs were assessed. For the entire tumor burden, SUL mean/max , SUV mean , tumor volume (TV), and the total activity in the VOI were obtained using tumor segmentation. A Spearman's rank correlation coefficient was used to investigate correlations between normal organ uptake and tumor burden., Results: There was no significant correlation between TV with the vast majority of the investigated organs (lacrimal glands, parotid glands, submandibular glands, spleen, and liver). Only the kidney showed significant correlation: With an isocontour threshold at 50 %, left kidney uptake parameters correlated significantly with TV (SUV mean , ρ = - 0.214 and SUL mean , ρ = - 0.176, p < 0.05, respectively)., Conclusions: Only a minimal sink effect with high tumor burden in patients imaged with [ 18 F]DCFPyL was observed. Other factors, such as a high intra-patient variability of normal organ uptake, may be a much more important consideration for personalized dosimetry with PSMA-targeted therapeutic agents structurally related to [ 18 F]DCFPyL than the tumor burden.

Intra-arterial (IA) infusion of mannitol induces osmotic blood-brain barrier opening (OBBBO) and that method has been used for decades to improve drug delivery to the brain. However, high variability of outcomes prevented vast clinical adoption. Studies on dynamic multi-scale imaging of OBBBO as well as extravasation of IA injected therapeutic agents are essential to develop strategies assuring precision and reproducibility of drug delivery. Intravital microscopy is increasingly used to capture the dynamics of biological processes at the molecular level in convenient mouse models. However, until now OBBBO has been achieved safely in subcortical structures, which prevented direct insight into the process of extravasation through the skull window. Here, we used our previously developed real-time MRI to adjust the procedure to achieve robust cortical OBBBO. We found that catheter-mediated delivery to the cortex from the ipsilateral carotid artery can be improved by temporarily occluding the contralateral carotid artery. The reproducibility and safety of the method were validated by MRI and histology. This experimental platform was further exploited for studying with intravital microscopy the extravasation of 0.58 kDa rhodamine and 153 kDa anti-VEGF monoclonal antibody (bevacizumab) upon IA injection. Dynamic imaging during IA infusion captured the spatiotemporal dynamic of infiltration for each molecule into the brain parenchyma upon OBBBO. Small-sized rhodamine exhibited faster and higher penetration than the antibody. Histological analysis showed some uptake of the monoclonal antibody after IA delivery, and OBBBO significantly amplified the extent of its uptake. For quantitative assessment of cortical uptake, bevacizumab was radiolabeled with zirconium-89 and infused intraarterially. As expected, OBBBO potentiated brain accumulation, providing 33.90 ± 9.06% of injected dose per gram of brain tissue (%ID/g) in the cortex and 17.09 ± 7.22%ID/g in subcortical structures. In contrast IA infusion with an intact BBB resulted in 3.56 ± 1.06%ID/g and 3.57 ± 0.59%ID/g in the same brain regions, respectively. This study established reproducible cortical OBBBO in mice, which enabled multi-photon microscopy studies on OBBBO and drug targeting. This approach helped demonstrate in a dynamic fashion extravasation of fluorescently-tagged antibodies and their effective delivery into the brain across an osmotically opened BBB., Competing Interests: Declaration of Competing Interest PW, MJ and MP are founders and hold equity in IntraArt, LLC and TiCom, LLC. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflicts of interest policies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Prostate cancer is primarily fatal after it becomes metastatic and castration-resistant despite novel combined hormonal and chemotherapeutic regimens. Hence, new therapeutic concepts and drug delivery strategies are urgently needed for the eradication of this devastating disease. Here we report the highly specific, in situ click chemistry driven pretargeted delivery of cytotoxic drug carriers to PSMA(+) prostate cancer cells. Anti-PSMA 5D3 mAb and its F(ab') 2 fragments were functionalized with trans -cyclooctene (TCO), labeled with a fluorophore, and used as pretargeting components. Human serum albumin (ALB) was loaded with the DM1 antitubulin agent, functionalized with PEGylated tetrazine (PEG 4 -Tz), labeled with a fluorophore, and used as the drug delivery component. The internalization kinetics of components and the therapeutic efficacy of the pretargeted click therapy were studied in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu control cells. The F(ab') 2 fragments were internalized faster than 5D3 mAb in PSMA(+) PC3-PIP cells. In the two-component pretargeted imaging study, both components were colocalized in a perinuclear location of the cytoplasm of PC3-PIP cells. Better colocalization was achieved when 5D3 mAb was used as the pretargeting component. Consecutively, the in vitro cell viability study shows a significantly higher therapeutic effect of click therapy in PC3-PIP cells when 5D3 mAb was used for pretargeting, compared to its F(ab') 2 derivative. 5D3 mAb has a longer lifetime on the cell surface, when compared to its F(ab') 2 analogue, enabling efficient cross-linking with the drug delivery component and increased efficacy. Pretargeting and drug delivery components were cross-linked via multiple bioorthogonal click chemistry reactions on the surface of PSMA(+) PC cells forming nanoclusters, which undergo fast cellular internalization and intracellular transport to perinuclear locations.

Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with 68 Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from 68 Ga- to 18 F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite 68 Ge/ 68 Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, 18 F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, 18 F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging 18 F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available 18 F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios., Competing Interests: Competing Interests: Martin G. Pomper is a coinventor on a patent covering [18F]DCFPyL and is entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. He has also received research funding from Progenics Phamaceuticals, the licensee of [18F]DCFPyL. Michael A. Gorin has served as a consultant to, and has received research funding from, Progenics Phamaceuticals. Steven P. Rowe has received research funding from Progenics Phamaceuticals., (© The author(s).)

Purpose: Imaging is limited in the evaluation of bacterial infection. Direct imaging of in situ bacteria holds promise for noninvasive diagnosis. We investigated the ability of a bacterial thymidine kinase inhibitor ([ 124 I]FIAU) to image pulmonary and musculoskeletal infections., Methods: Thirty-three patients were prospectively accrued: 16 with suspected musculoskeletal infection, 14 with suspected pulmonary infection, and 3 with known rheumatoid arthritis without infection. Thirty-one patients were imaged with [ 124 I]FIAU PET/CT and 28 with [ 18 F]FDG PET/CT. Patient histories were reviewed by an experienced clinician with subspecialty training in infectious diseases and were determined to be positive, equivocal, or negative for infection., Results: Sensitivity, specificity, positive-predictive value, negative-predictive value, and accuracy of [ 124 I]FIAU PET/CT for diagnosing infection were estimated as 7.7% to 25.0%, 0.0%, 50%, 0.0%, and 20.0% to 71.4% for musculoskeletal infections and incalculable-100.0%, 51.7% to 72.7%, 0.0% to 50.0%, 100.0%, and 57.1% to 78.6% for pulmonary infections, respectively. The parameters for [ 18 F]FDG PET/CT were 75.0% to 92.3%, 0.0%, 23.1% to 92.3%, 0.0%, and 21.4% to 85.7%, respectively, for musculoskeletal infections and incalculable to 100.0%, 0.0%, 0.0% to 18.2%, incalculable, and 0.0% to 18.2% for pulmonary infections, respectively., Conclusions: The high number of patients with equivocal clinical findings prevented definitive conclusions from being made regarding the diagnostic efficacy of [ 124 I]FIAU. Future studies using microbiology to rigorously define infection in patients and PET radiotracers optimized for image quality are needed.

Targeted radiopharmaceutical therapy (TRT) using α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)-targeted low-molecular-weight agents for 212 Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203 Pb. Methods: Five rationally designed low-molecular-weight ligands (L1-L5) were synthesized using the lysine-urea-glutamate scaffold, and PSMA inhibition constants were determined. Tissue biodistribution and SPECT/CT imaging of 203 Pb-L1- 203 Pb-L5 were performed on mice bearing PSMA(+) PC3 PIP and PSMA(-) PC3 flu flank xenografts. The absorbed radiation dose of the corresponding 212 Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of 212 Pb-L2 was evaluated in PSMA(+) PC3 PIP and PSMA(-) PC3 flu tumor models and in the PSMA(+) luciferase-expressing micrometastatic model. 212 Pb-L2 was also evaluated for dose-escalated, long-term toxicity. Results: All new ligands were obtained in high yield and purity. PSMA inhibitory activities ranged from 0.10 to 17 nM. 203 Pb-L1- 203 Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearance of 203 Pb-L1- 203 Pb-L5 was fast. The absorbed dose coefficients (mGy/kBq) of the tumor and kidneys were highest for 203 Pb-L5 (31.0, 15.2) and lowest for 203 Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for 203 Pb-L3 (3.2) and 203 Pb-L4 (3.6) than for the other agents, but with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h after injection. A proof-of-concept therapy study with a single administration of 212 Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(+) flank tumor model. 212 Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared with 177 Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion: 203 Pb-L1- 203 Pb-L5 demonstrated favorable pharmacokinetics for 212 Pb-based TRT. The antitumor efficacy of 212 Pb-L2 supports the corresponding 203 Pb/ 212 Pb theranostic pair for PSMA-based α-particle TRT in advanced PC., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Our purpose is to provide the results of a prospective study evaluating prostate-specific membrane antigen-targeted 18 F-DCFPyL (2-(3-{1-carboxy-5-[(6- 18 F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) PET/CT in patients with biochemical failure after radical prostatectomy for prostate cancer (PCa). Methods: Thirty-one patients with postprostatectomy serum prostate-specific antigen (PSA) levels of at least 0.2 ng/mL and negative conventional imaging results were enrolled in this study and imaged with 18 F-DCFPyL PET/CT. A consensus central review identified foci of radiotracer uptake consistent with sites of PCa. Descriptive statistics were used. Results: Twenty-one patients (67.7%) had at least 1 finding on 18 F-DCFPyL PET/CT consistent with a site of PCa. Imaging was positive in 59.1% of patients with a PSA level of less than 1.0 ng/mL and in 88.9% of patients with a PSA level of more than 1.0 ng/mL. The median SUV max across all lesions was 11.6 (range, 1.5-57.6). Conclusion: In this prospective study using the prostate-specific membrane antigen-targeted PET agent 18 F-DCFPyL, most patients with biochemical failure after radical prostatectomy had foci of suggestive uptake, even at low serum PSA levels., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Extensive research is currently being conducted into dynamic positron emission tomography (PET) acquisitions (including dynamic whole-body imaging) as well as extraction of radiomic features from imaging modalities. We describe a new PET viewing software known as Imager-4D that provides a facile means of viewing and analyzing dynamic PET data and obtaining associated quantitative metrics including radiomic parameters. The Imager-4D was programmed in the Java language utilizing the FX extensions. It is executable on any system for which a Java w/FX compliant virtual machine is available. The software incorporates the ability to view and analyze dynamic data acquired with different types of dynamic protocols. For image display, the program maintains a built-in library of 62 different lookup tables with monochromatic and full-color distributions. The Imager-4D provides multiple display layouts and can display fused images. Multiple methods of volume-of-interest (VOI) selection are available. Dynamic analysis features, such as image summation and full Patlak analysis, are also available. The user interface includes window width and level, blending, and zoom functionality. VOI sizes are adjustable and data from VOIs can either be displayed numerically or graphically within the software or exported. An example case of a 50-year-old woman with metastatic colorectal cancer and thyroiditis is included and demonstrates the steps for a user to obtain standard PET parameters, dynamic data, and radiomic features using selected VOIs. The Imager-4D represents a novel PET viewer that allows the user to view dynamic PET data, to derive dynamic and radiomic parameters from that data, and to combine dynamic data with radiomics ("dynomics"). The Imager-4D is available as a free download. This software has the potential to speed the adoption of advanced analysis of dynamic PET data into routine clinical use.

Purpose: Prostate carcinoma consists of tumor epithelium and malignant stroma. Until recently, diagnostic and therapeutic efforts have focused exclusively on targeting characteristics of the tumor epithelium, ignoring opportunities to target inflammatory infiltrate and extracellular matrix components. Prostate tumors are rich in tumor-associated macrophages (TAMs), which can be either of the cytotoxic M1 or protumorigenic M2 phenotype. We have quantified the proportion of each in seven common human prostate tumor lines grown subcutaneously in athymic nude mice and have imaged macrophage densities in vivo in xenografts derived from these lines., Procedures: A panel of seven human prostate cancer xenografts was generated in intact male athymic nude mice reflecting variable expression of the androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Mice were imaged ex vivo using near-infrared fluorescence (NIRF) imaging for PSMA expression and total macrophage densities to enable direct comparison between the two. Tumors were harvested for sectioning and additional staining to delineate M1 and M2 phenotype along with vascular density., Results: Macrophage polarization analysis of sections revealed that all xenografts were > 94% M2 phenotype, and the few M1-polarized macrophages present were confined to the periphery. Xenografts displaying the fastest growth were associated with the highest densities of macrophages while the slowest growing tumors were characterized by focal, tumor-infiltrating macrophage densities. Xenograft sections displayed a strong positive spatial relationship between macrophages, vasculature, and PSMA expression., Conclusions: Prostate TAM disposition can be imaged ex vivo and is associated with growth characteristics of a variety of tumor subtypes regardless of PSMA or AR expression.

Purpose: Stereotactic ablative radiation therapy (SABR) for oligometastatic prostate cancer (OMPC) may improve clinical outcomes, but current challenges in intrafraction tracking of multiple small targets limits treatment accuracy. A biology-guided radiation therapy (BgRT) delivery system incorporating positron emission tomography (PET) detectors is being developed to use radiotracer uptake as a biologic fiducial for intrafraction tumor tracking to improve geometric accuracy. This study simulates prostate-specific membrane antigen (PSMA)-directed BgRT using a cohort from our phase II randomized trial of SABR in men with recurrent hormone sensitive OMPC and compares dose distributions to clinical SABR (CSABR)., Methods and Materials: A research treatment planning system (RTPS) was used to replan 15 patients imaged with PSMA-targeted 18 F-DCFPyL PET/computed tomography and previously treated with CSABR using conventional linear accelerators (linacs). The RTPS models a prototype ring-mounted linac incorporating PET and kilo-voltage computed tomography imaging subsystems and can be used to optimize BgRT plans, as well as research SABR (RSABR) plans, which use the prototype linac without radiotracer guidance. CSABR, RSABR, and BgRT plans were compared in terms of maximum planning target volume (PTV) dose (D max ), mean dose to proximal organs at risk (D OAR ), conformity index, as well as voxel-wise correlation of dose with PET specific uptake values to investigate possible dose-painting effects., Results: RSABR and BgRT plans resulted in mean ± standard deviation increases in D max of 4 ± 11% ( P = .21) and 18 ± 15% ( P < .001) and reductions in D OAR of -20 ± 19% ( P <.001) and -10 ± 19% ( P = .02) compared with CSABR. Similar target coverage was maintained with conformity indices of 0.81 ± 0.04 ( P < .001) and 0.72 ± 0.08 ( P = .44) for RSABR and BgRT compared with 0.74 ± 0.08 for CSABR. Dose and log (specific uptake values) had Pearson correlation coefficients of 0.10 (CSABR), 0.16 (RSABR), and 0.31 (BgRT)., Conclusions: BgRT plans provided similar PTV coverage and conformity compared with CSABR while incorporating underlying PET activity. These results demonstrate feasibility of BgRT optimization enabling online PSMA-targeted, PET-based tracked dose delivery for OMPC., (© 2019 The Author(s).)

With the movement toward precision medicine in healthcare, recent studies of individuals with psychosis have begun to explore positron emission tomography (PET) as a tool to test for biochemical signatures that may distinguish subtypes of psychosis that guide subtype-specific therapeutic interventions. This review presents selected PET findings that exemplify early promise in using molecular imaging to predict treatment response, provide rationale for new therapeutic targets, and monitor target engagement in biomarker-defined subtypes of psychosis. PET data, among other data types, may prove useful in the scientific pursuit of identifying precision strategies to improve clinical outcomes for individuals with psychosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of 177 Lu., Methods: We synthesized 14 new PSMA-targeted, 177 Lu-labeled radioligands ( 177 Lu-L1- 177 Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(-) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for 177 Lu-L1, 177 Lu-L3, 177 Lu-L5 and 177 Lu-PSMA-617. Efficacy of 177 Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice., Results: Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. 177 Lu-L1, 177 Lu-L3 and 177 Lu-L5 demonstrated comparable uptake to 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. 177 Lu-L1, 177 Lu-L3 and 177 Lu-L5 also demonstrated efficient tumor regression at 8 weeks. 177 Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of 177 Lu-L1, most likely related to the fast renal clearance of this agent., Conclusions: 177 Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.

Recent years have witnessed an expanded use of single-photon emission CT and PET for a wide range of clinical applications, including imaging of brain abnormalities. As a result, molecular brain imaging is now being more extensively utilized in criminal cases, in particular in the sentencing phase of a trial. This perspective aims to provide a brief overview for the practicing radiologist of this expanded use of single-photon emission CT and PET in criminal cases and will discuss the role of radiology in this field., (Copyright © 2019 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18 F positron emission tomography (PET) DREADD radiotracer, [ 18 F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [ 18 F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.

Neuroendocrine tumors (NETs) are an extremely heterogenous group of malignancies with variable clinical behavior. Molecular imaging of patients with NETs allows for effective patient stratification and treatment guidance and is crucial in selection of targeted therapies. Positron emission tomography (PET) with the radiotracer L-[ 18 F]FDOPA is progressively being utilized for non-invasive in vivo visualization of NETs and pancreatic β-cell hyperplasia. While L-[ 18 F]FDOPA-PET is a valuable tool for disease detection and management, it also exhibits significant diagnostic limitations owing to its inherent physiological uptake in off-target tissues. We hypothesized that the D-amino acid structural isomer of that clinical tracer, D-[ 18 F]FDOPA, may exhibit superior clearance capabilities owing to a reduced in vivo enzymatic recognition and enzyme-mediated metabolism. Here, we report a side-by-side evaluation of D-[ 18 F]FDOPA with its counterpart clinical tracer, L-[ 18 F]FDOPA, for the non-invasive in vivo detection of NETs. In vitro evaluation in five NET cell lines, including invasive small intestinal neuroendocrine carcinomas (STC-1), insulinomas (TGP52 and TGP61), colorectal adenocarcinomas (COLO-320) and pheochromocytomas (PC12), generally indicated higher overall uptake levels of L-[ 18 F]FDOPA, compared to D-[ 18 F]FDOPA. While in vivo PET imaging and ex vivo biodistribution studies in PC12, STC-1 and COLO-320 mouse xenografts further supported our in vitro data, they also illustrated lower off-target retention and enhanced clearance of D-[ 18 F]FDOPA from healthy tissues. Cumulatively our results indicate the potential diagnostic applications of D-[ 18 F]FDOPA for malignancies where the utility of L-[ 18 F]FDOPA-PET is limited by the physiological uptake of L-[ 18 F]FDOPA, and suggest D-[ 18 F]FDOPA as a viable PET imaging tracer for NETs., Competing Interests: CONFLICTS OF INTEREST The authors do not have any conflicts of interest., (Copyright: © 2019 Narayan et al.)

Purpose: Objectives of the study are to analyze the correlation between [ 68 Ga]DOTATATE positron emission tomography (PET)/X-ray computed tomography (CT) measurements and various biological characteristics of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), and to determine optimal cutoff value of SUVmax (standard uptake value) to differentiate neuroendocrine tumors (NETs) and neuroendocrine cancers (NECs)., Procedures: Of the GEP-NEN cases (73 males, 53 females; age 18-77 years) with pathologically proven primary and/or metastatic lesions, 126 were studied. All of the short axes of lesions were larger than 0.5 cm in order to avoid the partial volume effect. Patients fasted for 6 h before the PET/CT scans. The dose of [ 68 Ga]DOTATATE was 100-200 MBq and the acquisition began at 1 h after injection. The lesion with the highest SUVmax in each patient was analyzed., Results: In the total sample, the sensitivity of [68Ga]DOTATATE was 69.05 %. The sensitivities were significantly different among G1, G2, and G3 groups (72.22 %, 91.53 %, and 40.82 %, respectively; p < 0.01). The SUVmax of the G3 group was lowest. We also found that the sensitivity and SUVmax were significantly higher (p < 0.05) in patients with pancreatic NENs (Pan-NENs) than in patients with gastrointestinal NENs (Gi-NENs) and unknown primary NENs (Up-NENs). A significant negative correlation between SUVmax and Ki-67 was found (r = - 0.429, p < 0.01). Using SUVmax to differentiate neuroendocrine tumors (NETs) and neuroendocrine cancers (NECs), the area under the ROC curve (AUC) was 0.771 and the cutoff value of SUVmax was 11.25 (sensitivity 79.2 %, specificity 65.3 %). However, Pan-NENs did not show any statistical significance results in correlation and ROC analysis., Conclusion: [ 68 Ga]DOTATATE PET/CT results showed a negative correlation with GEP-NEN cell proliferation and were complementary to Ki-67. Pan-NENs were different from Gi-NENs and Up-NENs when compared to somatostatin receptor expression.

Background: Prostate-specific membrane antigen (PSMA) is a rational target for noninvasive detection of recurrent prostate cancer (PCa) and for therapy of metastatic castration-resistant prostate cancer (mCRPC) with PSMA-targeted agents. Here we conducted serial measurements of PSMA expression on circulating tumor cells (CTCs) to evaluate patterns of longitudinal PSMA dynamics over the course of multiple sequential therapies., Methods: A retrospective investigation of men with mCRPC undergoing evaluation at medical oncology clinics at our institution assessed the dynamics of PSMA expression in the context of different systemic treatments administered sequentially. Eligibility included patients who began systemic therapies with androgen receptor (AR)-directed agents or taxane agents for whom peripheral blood samples were tested for CTC mRNA of AR splice variant-7 (AR-V7), prostate-specific antigen (PSA), and PSMA (with >2 CTC + results) in a CLIA-accredited laboratory., Results: From August 2015 to November 2017, we identified 96 eligible men. Fifteen had greater than or equal to 2 sequential therapies and evaluable CTC samples, greater than or equal to 1 expressing PSMA (PSMA+). Among the 15 patients included in this analysis, a total of 54 PSMA status evaluations were performed in the context of 48 therapies during a median follow-up of 18 months. At baseline, PSMA signal was detected ("positive") in 11 of 15 (73.3%) patients, while for 4 of 15 (26.7%) patients PSMA signal was undetectable ("negative"). In all but two patients, the baseline collection corresponded with a change in treatment. On the second assessment, PSMA increases were detected in all 4/4 (100%) PSMA-negative patients and 8 of 11 (72.7%) PSMA-positive patients. PSMA significantly decreased in a patient treated with 177 Lu-PSMA-617. Serum PSA declines were seen in 7 of 8 (88%) of the treatment periods where PSMA decreased., Conclusions: PSMA expression in CTCs is a dynamic marker. PSMA transcript declines appear to be associated with concurrent decreases in serum PSA. Sequential CTC sampling could provide a noninvasive response assessment to systemic treatment for mCRPC., (© 2019 Wiley Periodicals, Inc.)

Polyelectrolyte complex (PEC) nanoparticles assembled from plasmid DNA ( p DNA) and polycations such as linear polyethylenimine ( l PEI) represent a major nonviral delivery vehicle for gene therapy tested thus far. Efforts to control the size, shape, and surface properties of p DNA/polycation nanoparticles have been primarily focused on fine-tuning the molecular structures of the polycationic carriers and on assembly conditions such as medium polarity, pH, and temperature. However, reproducible production of these nanoparticles hinges on the ability to control the assembly kinetics, given the nonequilibrium nature of the assembly process and nanoparticle composition. Here we adopt a kinetically controlled mixing process, termed flash nanocomplexation (FNC), that accelerates the mixing of p DNA solution with polycation l PEI solution to match the PEC assembly kinetics through turbulent mixing in a microchamber. This achieves explicit control of the kinetic conditions for p DNA/ l PEI nanoparticle assembly, as demonstrated by the tunability of nanoparticle size, composition, and p DNA payload. Through a combined experimental and simulation approach, we prepared p DNA/ l PEI nanoparticles having an average of 1.3 to 21.8 copies of p DNA per nanoparticle and average size of 35 to 130 nm in a more uniform and scalable manner than bulk mixing methods. Using these nanoparticles with defined compositions and sizes, we showed the correlation of p DNA payload and nanoparticle formulation composition with the transfection efficiencies and toxicity in vivo . These nanoparticles exhibited long-term stability at -20 °C for at least 9 months in a lyophilized formulation, validating scalable manufacture of an off-the-shelf nanoparticle product with well-defined characteristics as a gene medicine.

Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Despite histological evidence in various solid tumor entities, available experience with CXCR4-directed diagnostics and endoradiotherapy mainly focuses on hematologic diseases. With the goal of expanding the application of CXCR4 theranostics to solid tumors, we aimed to elucidate the feasibility of CXCR4-targeted imaging in a variety of such neoplasms. Methods: Nineteen patients with newly diagnosed, treatment-naïve solid tumors including pancreatic adenocarcinoma or neuroendocrine tumor, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, and prostate cancer underwent [ 68 Ga]Pentixafor PET/CT. CXCR4-mediated uptake was assessed both visually and semi-quantitatively by evaluation of maximum standardized uptake values (SUV max ) of both primary tumors and metastases. With physiologic liver uptake as reference, tumor-to-background ratios (TBR) were calculated. [ 68 Ga]Pentixafor findings were further compared to immunohistochemistry and [ 18 F]FDG PET/CT. Results: On [ 68 Ga]Pentixafor PET/CT, 10/19 (52.6%) primary tumors were visually detectable with a median SUV max of 5.4 (range, 1.7-16.0) and a median TBR of 2.6 (range, 0.8-7.4), respectively. The highest level of radiotracer uptake was identified in a patient with cholangiocarcinoma (SUV max , 16.0; TBR, 7.4). The relatively low uptake on [ 68 Ga]Pentixafor was also noted in metastases, exhibiting a median SUV max of 4.5 (range, 2.3-8.8; TBR, 1.7; range, 1.0-4.1). A good correlation between uptake on [ 68 Ga]Pentixafor and histological derived CXCR4 expression was noted ( R = 0.62, P < 0.05). In the 3 patients in whom [ 18 F]FDG PET/CT was available, [ 68 Ga]Pentixafor exhibited lower uptake in all lesions. Conclusions: In this cohort of newly diagnosed, treatment-naïve patients with solid malignancies, CXCR4 expression as detected by [ 68 Ga]Pentixafor-PET/CT and immunohistochemistry was rather moderate. Thus, CXCR4-directed imaging may not play a major role in the management of solid tumors in the majority of patients.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most remarkable advances in cancer therapy in the last several decades. More than 300 adoptive T-cell therapy trials are ongoing, which is a testament to the early success and hope engendered by this line of investigation. Despite the enthusiasm, application of CAR T-cell therapy to solid tumours has had little success, although positive outcomes are increasingly being reported for these diseases. In this Series paper, we discuss the short-term strategies to improve CAR T-cell therapy responses, particularly for solid tumours, by combining CAR T-cell therapy with radiotherapy through the use of careful monitoring and non-invasive imaging. Through the use of imaging, we can gain greater mechanistic insights into the cascade of events that must unfold to enable tumour eradication by CAR T-cell therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Although single-photon-emitting radiotracers have long been the standard for renal functional molecular imaging, recent years have seen the development of positron emission tomography (PET) agents for this application. We provide an overview of renal radionuclide PET radiotracers, in particular focusing on novel 18 F-labelled and 68 Ga-labelled agents. Several reported PET imaging probes allow assessment of glomerular filtration rate, such as [ 68 Ga]ethylenediaminetetraacetic acid ([ 68 Ga]EDTA), [ 68 Ga]IRDye800-tilmanocept and 2-deoxy-2-[ 18 F]fluorosorbitol ([ 18 F]FDS)). The diagnostic performance of [ 68 Ga]EDTA has already been demonstrated in a clinical trial. [ 68 Ga]IRDye800-tilmanocept shows receptor-mediated binding to glomerular mesangial cells, which in turn may allow the monitoring of progression of diabetic nephropathy. [ 18 F]FDS shows excellent kidney extraction and excretion in rats and, as has been shown in the first study in humans. Further, due to its simple one-step radiosynthesis via the most frequently used PET radiotracer 2-deoxy-2-[ 18 F]fluoro-D-glucose, [ 18 F]FDS could be available at nearly every PET centre. A new PET radiotracer has also been introduced for the effective assessment of plasma flow in the kidneys: Re(CO) 3 -N-([ 18 F]fluoroethyl)iminodiacetic acid (Re(CO) 3 ([ 18 F]FEDA)). This compound demonstrates similar pharmacokinetic properties to its 99m Tc-labelled analogue [ 99m Tc](CO) 3 (FEDA). Thus, if there is a shortage of molybdenum-99, Re(CO) 3 ([ 18 F]FEDA would allow direct comparison with previous studies with 99m Tc. The PET radiotracers for renal imaging reviewed here allow thorough evaluation of kidney function, with the tremendous advantage of precise anatomical coregistration with simultaneously acquired CT images and rapid three-dimensional imaging capability.

Purpose: As has been previously reported, the somatostatin receptor (SSTR) imaging agent [ 68 Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotate ([ 68 Ga]DOTATATE) demonstrates lower uptake in normal organs in patients with a high neuroendocrine tumor (NET) burden. Given the higher SSTR affinity of [ 68 Ga] DOTATATE, we aimed to quantitatively investigate the biodistribution of [ 68 Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide ([ 68 Ga]DOTATOC) to determine a potential correlation between uptake in normal organs and NET burden., Procedures: Of the 44 included patients, 36/44 (82 %) patients demonstrated suspicious radiotracer uptake on [ 68 Ga] DOTATOC positron emission tomography (PET)/X-ray computed tomography (CT). Volumes of interest (VOIs) were defined for tumor lesions and normal organs (spleen, liver, kidneys, adrenals). Mean body weight corrected standardized uptake value (SUV mean ) for normal organs was assessed and was used to calculate the corresponding mean specific activity uptake (Upt: fraction of injected activity per kg of tissue). For the entire tumor burden, SUV mean , maximum standardized uptake value (SUV max ), and the total mass (TBM) was calculated and the decay corrected tumor fractional uptake (TBU) was assessed. A Spearman's rank correlation coefficient was used to determine the correlations between normal organ uptake and tumor burden., Results: The median SUV mean was 18.7 for the spleen (kidneys, 9.2; adrenals, 6.8; liver, 5.6). For tumor burden, the median values were SUV mean 6.9, SUV max 35.5, TBM 42.6 g, and TBU 1.2 %. With increasing volume of distribution, represented by lean body mass and body surface area (BSA), Upt decreased in kidneys, liver, and adrenal glands and SUV mean increased in the spleen. Correlation improved only for both kidneys and adrenals when the influence of the tumor uptake on the activity available for organ uptake was taken into account by the factor 1/(1-TBU). TBU was neither predictive for SUV mean nor for Upt in any of the organs. The distribution of organ Upt vs. BSA/(1-TBU) were not different for patients with minor TBU (<3 %) vs. higher TBU (>7 %), indicating that the correlations observed in the present study are explainable by the body size effect. High tumor mass and uptake mitigated against G1 NET., Conclusions: There is no significant impact on normal organ biodistribution with increasing tumor burden on [ 68 Ga] DOTATOC PET/CT. Potential implications include increased normal organ dose with [ 177 Lu-DOTA] 0 -D-Phe 1 -Tyr 3 -Octreotide and decreased absolute lesion detection with [ 68 Ga] DOTATOC in high NET burden.

Backgorund: Quantification of myocardial blood flow (MBF) by positron emission tomography (PET) is important for investigation of angina in hypertrophic cardiomyopathy (HCM). Several software programs exist for MBF quantification, but they have been mostly evaluated in patients (with normal cardiac geometry), referred for evaluation of coronary artery disease (CAD). Software performance has not been evaluated in HCM patients who frequently have hyperdynamic LV function, LV outflow tract (LVOT) obstruction, small LV cavity size, and variation in the degree/location of LV hypertrophy., Aim: We compared results of MBF obtained using PMod, which permits manual segmentation, to those obtained by FDA-approved QPET software which has an automated segmentation algorithm., Methods: 13 N-ammonia PET perfusion data were acquired in list mode at rest and during pharmacologic vasodilation, in 76 HCM patients and 10 non-HCM patients referred for evaluation of CAD (CAD group.) Data were resampled to create static, ECG-gated and 36-frame-dynamic images. Myocardial flow reserve (MFR) and MBF (in ml/min/g) were calculated using QPET and PMod softwares., Results: All HCM patients had asymmetric septal hypertrophy, and 50% had evidence of LVOT obstruction, whereas non-HCM patients (CAD group) had normal wall thickness and ejection fraction. PMod yielded significantly higher values for global and regional stress-MBF and MFR than for QPET in HCM. Reasonably fair correlation was observed for global rest-MBF, stress-MBF, and MFR using these two softwares (rest-MBF: r = 0.78; stress-MBF: r = 0.66.; MFR: r = 0.7) in HCM patients. Agreement between global MBF and MFR values improved when HCM patients with high spillover fractions (> 0.65) were excluded from the analysis (rest-MBF: r = 0.84; stress-MBF: r = 0.72; MFR: r = 0.8.) Regionally, the highest agreement between PMod and QPET was observed in the LAD territory (rest-MBF: r = 0.82, Stress-MBF: r = 0.68) where spillover fraction was the lowest. Unlike HCM patients, the non-HCM patients (CAD group) demonstrated excellent agreement in MBF/MFR values, obtained by the two softwares, when patients with high spillover fractions were excluded (rest-MBF: r = 0.95; stress-MBF: r = 0.92; MFR: r = 0.95)., Conclusions: Anatomic characteristics specific to HCM hearts contribute to lower correlations between MBF/MFR values obtained by PMod and QPET, compared with non-HCM patients. These differences indicate that PMod and QPET cannot be used interchangeably for MBF/MFR analyses in HCM patients.

Introduction: We have recently shown that intracerebral delivery of an anti-VEGF monoclonal antibody bevacizumab using an intra-arterial (IA) infusion is more effective than intravenous administration. While antibodies are quickly emerging as therapeutics, their disadvantages such as large size, production logistics and immunogenicity motivate search for alternatives. Thus we have studied brain uptake of nanobodies and polyamidoamine (PAMAM) dendrimers., Methods: Nanobodies were conjugated with deferoxamine (DFO) to generate NB(DFO) 2 . Generation-4 PAMAM dendrimers were conjugated with DFO, and subsequently primary amines were capped with butane-1,2-diol functionalities to generate G4(DFO) 3 (Bdiol) 110 . Resulting conjugates were radiolabeled with zirconium-89. Brain uptake of 89 ZrNB(DFO) 2 and 89 ZrG4(DFO) 3 (Bdiol) 110 upon carotid artery vs tail vein infusions with intact BBB or osmotic blood-brain barrier opening (OBBBO) with mannitol in mice was monitored by dynamic positron emission tomography (PET) over 30 min to assess brain uptake and clearance, followed by whole-body PET-CT (computed tomography) imaging at 1 h and 24 h post-infusion (pi). Imaging results were subsequently validated by ex-vivo biodistribution., Results: Intravenous administration of 89 ZrNB(DFO) 2 and 89 ZrG4(DFO) 3 (Bdiol) 110 resulted in their negligible brain accumulation regardless of BBB status and timing of OBBBO. Intra-arterial (IA) administration of 89 ZrNB(DFO) 2 dramatically increased its brain uptake, which was further potentiated with prior OBBBO. Half of the initial brain uptake was retained after 24 h. In contrast, IA infusion of 89 ZrG4(DFO) 3 (Bdiol) 110 resulted in poor initial accumulation in the brain, with complete clearance within 1 h of administration. Ex-vivo biodistribution results reflected those on PET-CT., Conclusions: IA delivery of nanobodies might be an attractive therapeutic platform for CNS disorders where prolonged intracranial retention is necessary.

Objective: Complete surgical resection of metastatic sites has been shown to prolong survival in select patients with oligometastatic RCC. This treatment strategy is dependent upon the accurate characterization of a patient's extent of disease. The objective of this study was to explore the utility of PSMA-targeted 18 F-DCFPyL PET/CT in patients with presumed oligometastatic clear cell RCC., Methods: This is a subset analysis of a prospective study in which patients with RCC were imaged with 18 F-DCFPyL PET/CT (ClinicalTrials.gov identifier NCT02687139). In the present analysis, patients with oligometastatic clear cell RCC, defined as ≤ 3 metastatic lesions on conventional imaging, were evaluated. 18 F-DCFPyL PET/CT scans were reviewed for sites of disease and compared to conventional imaging., Results: The final cohort included 14 patients with oligometastatic clear cell RCC. Conventional imaging revealed 21 metastatic lesions and 3 primary tumors. 18 F-DCFPyL PET/CT detected 29 sites of metastatic disease and 3 primary tumors. Of the 21 metastatic lesions detected on conventional imaging, 17 (81.0%) had radiotracer uptake. Additionally, all 3 primary tumors had radiotracer uptake. In 4 (28.6%) patients a total of 12 more lesions were identified on 18 F-DCFPyL PET/CT than conventional imaging. Notably, 3 (21.4%) patients were no longer considered oligometastatic. The detection rates of conventional imaging and 18 F-DCFPyL PET/CT for identifying sites of disease were 66.7% and 88.9%, respectively., Conclusions: PSMA-targeted PET/CT appears to aid in the identification of patients with oligometastatic clear cell RCC. If borne out in future studies, this suggests that PSMA-targeted imaging has the potential to help select candidates for metastasis-directed therapy.

The theranostic concept represents a paradigmatic example of personalized treatment. It is based on the use of radiolabeled compounds which can be applied for both diagnostic molecular imaging and subsequent treatment, using different radionuclides for labelling. Clinically relevant examples include somatostatin receptor (SSTR)-targeted imaging and therapy for the treatment of neuroendocrine tumors (NET), as well as prostate-specific membrane antigen (PSMA)-targeted imaging and therapy for the treatment of prostate cancer (PC). As such, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy using positron emission tomography (PET). While interpreting PSMA- or SSTR-targeted PET/computed tomography scans, the reader has to navigate certain pitfalls, including (I.) varying normal biodistribution between different PSMA- and SSTR-targeting PET radiotracers, (II.) varying radiotracer uptake in numerous kinds of both benign and malignant lesions, and (III.) resulting false-positive and false-negative findings. Thus, two novel reporting and data system (RADS) classifications for PSMA- and SSTR-targeted PET imaging (PSMA- and SSTR-RADS) have been recently introduced under the umbrella term molecular imaging reporting and data systems (MI-RADS). Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e., if the reader is familiar with one system, the other system can readily be applied. Learning objectives of the present case-based review are as follows: (I.) the theranostic concept for the treatment of NET and PC will be briefly introduced, (II.) the most common pitfalls on PSMA- and SSTR-targeted PET/CT will be identified, (III.) the novel framework system for theranostic radiotracers (MI-RADS) will be explained, applied to complex clinical cases and recent studies in the field will be highlighted. Finally, current treatment strategies based on MI-RADS will be proposed, which will demonstrate how such a generalizable framework system truly paves the way for clinically meaningful molecular imaging-guided treatment of either PC or NET. Thus, beyond an introduction of MI-RADS, the present review aims to provide an update of recently published studies which have further validated the concept of structured reporting systems in the field of theranostics.

Chimeric antigen receptor (CAR) T cell therapy for hematologic malignancies is fraught with several unknowns, including number of functional T cells that engage target tumor, durability and subsequent expansion and contraction of that engagement, and whether toxicity can be managed. Non-invasive, serial imaging of CAR T cell therapy using a reporter transgene can address those issues quantitatively. We have transduced anti-CD19 CAR T cells with the prostate-specific membrane antigen (PSMA) because it is a human protein with restricted normal tissue expression and has an expanding array of positron emission tomography (PET) and therapeutic radioligands. We demonstrate that CD19-tPSMA (N9del) CAR T cells can be tracked with [ 18 F]DCFPyL PET in a Nalm6 model of acute lymphoblastic leukemia. Divergence between the number of CD19-tPSMA (N9del) CAR T cells in peripheral blood and bone marrow and those in tumor was evident. These findings underscore the need for non-invasive repeatable monitoring of CAR T cell disposition clinically.

The continuing adoption of prostate specific membrane antigen (PSMA)-targeted PET for prostate cancer molecular imaging requires imagers and clinicians alike to be aware of the increasing number of potential interpretive pitfalls that have been reported. This review summarizes and illustrates the spectrum of benign and malignant nonprostatic conditions with high PSMA-radiotracer uptake that may be mistaken for sites of prostate cancer and also discusses potential false negatives. We discuss the recent literature on the effect of androgen deprivation therapy on lesion detection. Furthermore, we briefly review the recently proposed structured reporting systems for the standardized interpretation of PSMA-targeted PET that can guide both imaging specialists and referring clinicians in the appropriate interpretation and work-up of pitfalls., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [ 68 Ga]Pentixafor. Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [ 68 Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients. Results: [ 68 Ga]Pentixafor PET/CT was visually positive in all cases. SUV mean and SUV max were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR mean and TBR max were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors. Conclusion: Non-invasive imaging of CXCR4 expression using [ 68 Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.

The prostate-specific membrane antigen (PSMA) is a validated target for detection and management of prostate cancer (PC). It has also been utilized for targeted drug delivery through antibody-drug conjugates and polymeric micelles. Polyamidoamine (PAMAM) dendrimers are emerging as a versatile platform in a number of biomedical applications due to their unique physicochemical properties, including small size, large number of reactive terminal groups, bulky interior void volume, and biocompatibility. Here, we report the synthesis of generation 4 PSMA-targeted PAMAM dendrimers [G4(MP-KEU)] and evaluation of their targeting properties in vitro and in vivo using an experimental model of PC. A facile, one-pot synthesis gave nearly neutral nanoparticles with a narrow size distribution of 5 nm in diameter and a molecular weight of 27.3 kDa. They exhibited in vitro target specificity with a dissociation constant ( K d ) of 0.32 ± 0.23 μm and preferential accumulation in PSMA + PC3 PIP tumors versus isogenic PSMA - PC3 flu tumors. Positron emission tomography-computed tomography imaging and ex vivo biodistribution studies of dendrimers radiolabeled with 64 Cu, [ 64 Cu]G4(MP-KEU), demonstrated high accumulation in PSMA + PC3 PIP tumors at 24 h post-injection (45.83 ± 20.09% injected dose per gram of tissue, %ID/g), demonstrating a PSMA + PC3 PIP/PSMA - PC3 flu ratio of 7.65 ± 3.35. Specific accumulation of G4(MP-KEU) and [ 64 Cu]G4(MP-KEU) in PSMA + PC3 PIP tumors was inhibited by the known small-molecule PSMA inhibitor, ZJ-43. On the contrary, G4(Ctrl), control dendrimers without PSMA-targeting moieties, showed comparable low accumulation of ∼1%ID/g in tumors irrespective of PSMA expression, further confirming PSMA + tumor-specific uptake of G4(MP-KEU). These results suggest that G4(MP-KEU) may represent a suitable scaffold by which to target PSMA-expressing tissues with imaging and therapeutic agents.

Purpose: Diagnosis and therapeutic monitoring of chronic bacterial infection requires methods to detect and localize sites of infection accurately. Complement C3 activation fragments are generated and covalently bound to selective bacterial pathogens during the immune response and can serve as biomarkers of ongoing bacterial infection. We have developed several probes for detecting tissue-bound C3 deposits, including a monoclonal antibody (mAb 3d29) that recognizes the tissue-bound terminal processing fragments iC3b and C3d but does not recognize native circulating C3 or tissue-bound C3b., Procedures: To determine whether mAb 3d29 could be used to detect chronic Mycobacterium tuberculosis infection non-invasively, aerosol-infected female C3HeB/FeJ mice were injected with [ 125 I]3d29 mAb and either imaged using single-photon emission computed tomography (SPECT)/X-ray computed tomography (CT) imaging at 24 and 48 h after radiotracer injection or being subjected to biodistribution analysis., Results: Discrete lesions were detected by SPECT/CT imaging in the lungs and spleens of infected mice, consistent with the location of granulomas in the infected animals as detected by CT. Low-level signal was seen in the spleens of uninfected mice and no signal was seen in the lungs of healthy mice. Immunofluorescence microscopy revealed that 3d29 in the lungs of infected mice co-localized with aggregates of macrophages (detected with anti-CD68 antibodies). 3d29 was detected in the cytoplasm of macrophages, consistent with the location of internalized M. tuberculosis. 3d29 was also present within alveolar epithelial cells, indicating that it detected M. tuberculosis phagocytosed by other CD68-positive cells. Healthy controls showed very little retention of fluorescent or radiolabeled antibody across tissues. Radiolabeled 3d29 compared with radiolabeled isotype control showed a 3.5:1 ratio of increased uptake in infected lungs, indicating specific uptake by 3d29., Conclusion: 3d29 can be used to detect and localize areas of infection with M. tuberculosis non-invasively by 24 h after radiotracer injection and with high contrast.

Purpose: To investigate the utility of prostate-specific membrane antigen (PSMA)-targeted [ 18 F]DCFPyL positron emission tomography (PET)/X-ray computed tomography (CT) imaging for the detection of sites of disease in patients with metastatic non-clear cell renal cell carcinoma (RCC)., Procedures: Eight patients with metastatic non-clear cell RCC underwent imaging with PSMA-targeted [ 18 F]DCFPyL PET/CT. Imaged RCC histologic subtypes included papillary RCC (n = 3), chromophobe RCC (n = 2), unclassified RCC (n = 2), and Xp11 translocation RCC (n = 1). Using comparison to conventional CT and/or magnetic resonance imaging as reference, two radiologists with expertise in nuclear medicine identified putative sites of disease on [ 18 F]DCFPyL PET/CT and classified each lesion as having no radiotracer uptake, equivocal uptake, or definitive uptake., Resuts: In total, 73 metastatic sites and 3 primary tumors compatible with sites of non-clear cell RCC were identified on conventional imaging. Metastatic sites of disease included lymph nodes (n = 40), venous thrombi (n = 3), pulmonary nodules (n = 10), bone lesions (n = 15), brain lesions (n = 3), and retroperitoneal masses (n = 2). Only 10 of the 73 lesions (13.7 %) were classified as having definitive radiotracer uptake (median SUV max  = 3.25, range = 1.2-9.5), 14 lesions (19.2 %) had equivocal uptake (median SUV max  = 2.85, range = 0.5-6.5), and 49 lesions (67.1 %) had no definitive uptake above background (median SUV max  = 1.7, range = 0.2-3.0). The three primary renal tumors demonstrated lower radiotracer avidity relative to surrounding normal renal parenchyma., Conclusions: A small proportion of sites of non-clear cell RCC showed uptake of the PSMA-targeted radiotracer [ 18 F]DCFPyL. Unlike for clear cell RCC, the results of this study indicate that PSMA-based PET is not appropriate for imaging other RCC subtypes.