[99mTc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience.

PURPOSE: The clinical success non-invasive imaging of CXCR4 expression using [68 Ga]Ga-PentixaFor-PET warrants an expansion of the targeting concept towards conventional scintigraphy/SPECT with their lower cost and general availability. To this aim, we developed and comparatively evaluated a series of 99mTc-labeled cyclic pentapeptides based on the PentixaFor scaffold. METHODS: Six mas3-conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa3 linkers (L1-L6) as well as the corresponding HYNIC- and N4-analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC50 and IC50inv) were carried out using Jurkat T cell lymphoma cells and [125I]FC-131 as radioligand. Internalization kinetics were investigated using hCXCR4-overexpressing Chem-1 cells. Biodistribution studies and small animal SPECT/CT imaging (1 h p.i.) were carried out using Jurkat xenograft bearing CB17/SCID mice. Based on the preclinical results, [99mTc]Tc-N4-L6-CPCR4 ([99mTc]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [99mTc]Tc-N4-L6-CPCR4 SPECT/planar imaging with individual dosimetry. RESULTS: Of the six mas3-conjugated peptides, mas3-L6-CPCR4 (mas3-dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC50 = 5.0 ± 1.3 nM). Conjugation with N4 (N4-L6-CPCR4) further improved hCXCR4 affinity to 0.6 ± 0.1 nM. [99mTc]Tc-N4-L6-CPCR4 also showed the most efficient internalization (97% of total cellular activity at 2 h) and the highest tumor accumulation (8.6 ± 1.3% iD/g, 1 h p.i.) of the compounds investigated. Therefore, [99mTc]Tc-N4-L6-CPCR4 (termed [99mTc]Tc-PentixaTec) was selected for first-in-human application. [99mTc]Tc-PentixaTec was well tolerated, exhibits a favorable biodistribution and dosimetry profile (2.1-3.4 mSv per 500 MBq) and excellent tumor/background ratios in SPECT and planar imaging. CONCLUSION: The successive optimization of the amino acid composition of the linker structure and the N-terminal 99mTc-labeling strategies (mas3 vs HYNIC vs N4) has provided [99mTc]Tc-PentixaTec as a novel, highly promising CXCR4-targeted SPECT agent for clinical application. With its excellent CXCR4 affinity, efficient internalization, high uptake in CXCR4-expressing tissues, suitable clearance/biodistribution characteristics, and favorable human dosimetry, it holds great potential for further clinical use.

PSMA PET/CT: joint EANM procedure guideline/SNMMI procedure standard for prostate cancer imaging 2.0.

Here we aim to provide updated guidance and standards for the indication, acquisition, and interpretation of PSMA PET/CT for prostate cancer imaging. Procedures and characteristics are reported for a variety of available PSMA small radioligands. Different scenarios for the clinical use of PSMA-ligand PET/CT are discussed. This document provides clinicians and technicians with the best available evidence, to support the implementation of PSMA PET/CT imaging in research and routine practice.

Molecular Imaging of Inflammation and Fibrosis in Pressure Overload Heart Failure.

[Figure: see text].

Diverse PSMA expression in primary prostate cancer: reason for negative [68Ga]Ga-PSMA PET/CT scans? Immunohistochemical validation in 40 surgical specimens.

PURPOSE: The purpose of this study was to immunohistochemically validate the primary tumor PSMA expression in prostate cancer (PCa) patients imaged with [68Ga]Ga-PSMA PET/CT prior to surgery, with special consideration of PET-negative cases. METHODS: The study included 40 men with newly diagnosed treatment-naïve PCa imaged with [68Ga]Ga-PSMA I&T PET/CT as part of the diagnostic work-up prior to radical prostatectomy. All primary tumors were routinely stained with H&E. In addition, immunohistochemical staining of PSMA was performed and the immunoreactive score (IRS) was computed as semiquantitative measure. Subsequently, imaging findings were correlated to histopathologic results. RESULTS: Eighty-three percent (33/40) of patients presented focal uptake of [68Ga]Ga-PSMA I&T in the primary tumor in at least one prostate lobe. Among PSMA-PET positive patients, one-third had lymph node metastases (LNM) detected by post-operative histopathology, while in PET negative patients, only 1 out of 7 presented with regional LN involvement; PSMA-avid distant lesions, predominantly in bones, were observed in 15% and 0% of patients, respectively. The median IRS classification of PSMA expression in tumor tissue was 2 (range, 1-3) both in PSMA-PET positive and negative prostate lobes, with significantly different interquartile range: 2-3 vs. 2-2, respectively (p = 0.03). The median volume of PSMA-PET positive tumors was 5.4 mL (0.2-32.9) as compared to 1.6 mL (0.3-18.3) of PET-negative tumors (p < 0.001). There was a significant but weak correlation between SUVmax and percentage of PSMA-positive tumor cells (r = 0.46, p < 0.001). A total of 35/44 (~80%) lobes were positive in PSMA-PET imaging, when a cut-off percentage of PSMA-positive cells was ≥ 90%, while 19/36 (~53%) lobes with < 90% PSMA-positive cells were PSMA-PET negative. CONCLUSION: Positive [68Ga]Ga-PSMA I&T PET/CT scan of primary tumor of PCa results from a combination of factors, such as homogeneity and intensity of PSMA expression, tumor volume and grade, with a cutoff value of ≥ 90% PSMA-positive cells strongly determining PET-positivity. Focal accumulation of [68Ga]Ga-PSMA in the primary tumor may correlate positively with aggressiveness of prostate cancer, harboring higher risk of regional LN involvement and distant metastatic spread.

Multiparametric PET and MRI of myocardial damage after myocardial infarction: correlation of integrin αvß3 expression and myocardial blood flow.

PURPOSE: Increased angiogenesis after myocardial infarction is considered an important favorable prognostic parameter. The αvß3 integrin is a key mediator of cell-cell and cell-matrix interactions and an important molecular target for imaging of neovasculature and repair processes after MI. Thus, imaging of αvß3 expression might provide a novel biomarker for assessment of myocardial angiogenesis as a prognostic marker of left ventricular remodeling after MI. Currently, there is limited data available regarding the association of myocardial blood flow and αvß3 integrin expression after myocardial infarction in humans. METHODS: Twelve patients were examined 31 ± 14 days after MI with PET/CT using [18F]Galacto-RGD and [13N]NH3 and with cardiac MRI including late enhancement on the same day. Normal myocardium (remote) and areas of infarction (lesion) were identified on the [18F]Galacto-RGD PET/CT images by correlation with [13N]NH3 PET and cardiac MRI. Lesion/liver-, lesion/blood-, and lesion/remote ratios were calculated. Blood flow and [18F]Galacto-RGD uptake were quantified and correlated for each myocardial segment (AHA 17-segment model). RESULTS: In 5 patients, increased [18F]Galacto-RGD uptake was notable within or adjacent to the infarction areas with a lesion/remote ratio of 46% (26-83%; lesion/blood 1.15 ± 0.06; lesion/liver 0.61 ± 0.18). [18F]Galacto-RGD uptake correlated significantly with infarct size (R = 0.73; p = 0.016). Moreover, it correlated significantly with restricted blood flow for all myocardial segments (R = - 0.39; p < 0.0001) and even stronger in severely hypoperfused areas (R = - 0.75; p < 0.0001). CONCLUSION: [18F]Galacto-RGD PET/CT allows the visualization and quantification of myocardial αvß3 expression as a key player in angiogenesis in a subset of patients after MI. αvß3 expression was more pronounced in patients with larger infarcts and was generally more intense but not restricted to areas with more impaired blood flow, proving that tracer uptake was largely independent of unspecific perfusion effects. Based on these promising results, larger prospective studies are warranted to evaluate the potential of αvß3 imaging for assessment of myocardial angiogenesis and prediction of ventricular remodeling.

18F-FIBT may expand PET for ß-amyloid imaging in neurodegenerative diseases.

18F-FIBT, 2-(p-Methylaminophenyl)-7-(2-[18F]fluoroethoxy)imidazo-[2,1-b]benzothiazole, is a new selective PET tracer under clinical investigation to specifically image ß-amyloid depositions (Aß) in humans in-vivo that binds to Aß with excellent affinity (Kd 0.7 ± 0.2) and high selectivity over tau and α-synuclein aggregates (Ki > 1000 nM). We aimed to characterize 18F-FIBT in a series of patients with different clinical-pathophysiological phenotypes and to compare its binding characteristics to the reference compound PiB. Six patients (mild late-onset and moderate early-onset AD dementia, mild cognitive impairment due to AD, intermediate likelihood, mild behavioral variant of frontotemporal dementia, subjective memory impairment without evidence of neurodegeneration, and mild dementia due to Posterior Cortical Atrophy) underwent PET imaging with 18F-FIBT on PET/MR. With the guidance of MRI, PET images were corrected for partial volume effect, time-activity curves (TACs) of regions of interest (ROIs) were extracted, and non-displaceable binding potentials (BPnd), standardized uptake value ratios (SUVR), and distribution volume ratio (DVR) were compared. Specific binding was detected in the cases with evidence of the AD pathophysiological process visualized in images of BPnd, DVR and SUVR, consistently with patterns of different tracers in previous studies. SUVR showed the highest correlation with clinical severity. The previous preclinical characterization and the results of this case series suggest the clinical usefulness of FIBT as a selective and highly affine next-generation 18F-labeled tracer for amyloid-imaging with excellent pharmacokinetics in the diagnosis of neurodegenerative diseases. The results compare well to the gold standard PiB and hence support further investigation in larger human samples.

Correction: 18F-FIBT may expand PET for ß-amyloid imaging in neurodegenerative diseases.

The author listing has been updated to indicate that Timo Grimmer and Kuangyu Shi are equally contributing authors.

Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals.

BACKGROUND: Leukocyte subtypes bear distinct pro-inflammatory, reparative, and regulatory functions. Imaging inflammation provides information on disease prognosis and may guide therapy, but the cellular basis of the signal remains equivocal. We evaluated leukocyte subtype specificity of characterized clinically relevant inflammation-targeted radiotracers. METHODS AND RESULTS: Leukocyte populations were purified from blood- and THP-1-derived macrophages were polarized into M1-, reparative M2a-, or M2c-macrophages. In vitro uptake assays were conducted using tracers of enhanced glucose or amino acid metabolism and molecular markers of inflammatory cells. Both 18F-deoxyglucose (18F-FDG) and the labeled amino acid 11C-methionine (11C-MET) displayed higher uptake in neutrophils and monocytes compared to other leukocytes (P = 0.005), and markedly higher accumulation in pro-inflammatory M1-macrophages compared to reparative M2a-macrophages (P < 0.001). Molecular tracers 68Ga-DOTATATE targeting the somatostatin receptor type 2 and 68Ga-pentixafor targeting the chemokine receptor type 4 (CXCR4) exhibited broad uptake by leukocyte subpopulations and polarized macrophages with highest uptake in T-cells/natural killer cells and B-cells compared to neutrophils. Mitochondrial translocator protein (TSPO)-targeted 18F-flutriciclamide selectively accumulated in monocytes and pro-inflammatory M1 macrophages (P < 0.001). Uptake by myocytes and fibroblasts tended to be higher for metabolic radiotracers. CONCLUSIONS: The different in vitro cellular uptake profiles may allow isolation of distinct phases of the inflammatory pathway with specific inflammation-targeted radiotracers. The pathogenetic cell population in specific inflammatory diseases should be considered in the selection of an appropriate imaging agent.

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.

Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

Mapping the Binding Interface of PET Tracer Molecules and Alzheimer Disease Aß Fibrils by Using MAS Solid-State NMR Spectroscopy.

Positron emission tomography (PET) tracer molecules like thioflavin T specifically recognize amyloid deposition in brain tissue by selective binding to hydrophobic or aromatic surface grooves on the ß-sheet surface along the fibril axis. The molecular basis of this interaction is, however, not well understood. We have employed magic angle spinning (MAS) solid-state NMR spectroscopy to characterize Aß-PET tracer complexes at atomic resolution. We established a titration protocol by using bovine serum albumin as a carrier to transfer hydrophobic small molecules to Aß(1-40) fibrillar aggregates. The same Aß(1-40) amyloid fibril sample was employed in subsequent titrations to minimize systematic errors that potentially arise from sample preparation. In the experiments, the small molecules 13 C-methylated Pittsburgh compound B (PiB) as well as a novel Aß tracer based on a diarylbithiazole (DABTA) scaffold were employed. Classical 13 C-detected as well as proton-detected spectra of protonated and perdeuterated samples with back-substituted protons, respectively, were acquired and analyzed. After titration of the tracers, chemical-shift perturbations were observed in the loop region involving residues Gly25-Lys28 and Ile32-Gly33, thus suggesting that the PET tracer molecules interact with the loop region connecting ß-sheets ß1 and ß2 in Aß fibrils. We found that titration of the PiB derivatives suppressed fibril polymorphism and stabilized the amyloid fibril structure.

Image-Guided Surgery: Are We Getting the Most Out of Small-Molecule Prostate-Specific-Membrane-Antigen-Targeted Tracers?

Expressed on virtually all prostate cancers and their metastases, the transmembrane protein prostate-specific membrane antigen (PSMA) provides a valuable target for the imaging of prostate cancer. Not only does PSMA provide a target for noninvasive diagnostic imaging, e.g., PSMA-positron emission tomography (PSMA-PET), it can also be used to guide surgical resections of PSMA-positive lesions. The latter characteristic has led to the development of a plethora of PSMA-targeted tracers, i.e., radiolabeled, fluorescent, or hybrid. With image-guided surgery applications in mind, this review discusses these compounds based on clinical need. Here, the focus is on the chemical aspects (e.g., imaging label, spacer moiety, and targeting vector) and their impact on in vitro and in vivo tracer characteristics (e.g., affinity, tumor uptake, and clearance pattern).

68Ga-PSMA I&T PET/CT for primary staging of prostate cancer.

PURPOSE: The present study is based on a retrospective analysis of Gallium-68 (68Ga)-labelled prostate-specific membrane antigen (68Ga-PSMA I&T) PET/CT performed in newly diagnosed, treatment-naïve prostate cancer (PCa) patients prior to definitive treatment. METHODS: A total of 82 men were included in the study and were imaged with 68Ga-PSMA I&T PET/CT to assess the distribution of PSMA-avid disease for staging purposes (11 with low-risk, 32 with intermediate-risk, and 39 with high-risk PCa). Forty patients (20 with intermediate- and 20 with high-risk disease) underwent subsequent radical prostatectomy with extended pelvic lymph node dissection which allowed for correlation of imaging findings with histopathologic data. RESULTS: PSMA-positive disease was detected in 83% of patients with 66/82 (80.5%) primary tumours being visualized. PSMA-avid lymph nodes were recorded in 17/82 patients (20.7%, 3 with intermediate-risk and 14 with high-risk PCa); distant disease was found in 14/82 subjects (17.1%, 2 with intermediate-risk and 12 with high-risk PCa). No extraprostatic disease was found in low-risk PCa. SUVmax of primary tumours showed a weak but significant correlation with serum PSA values (r = 0.51, p < 0.001) and Gleason scores (GSC; r = 0.35, p = 0.001), respectively. In correlation with histopathology, calculated per-region sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detection of lymph node metastases were 35.0%, 98.4%, 63.6%, 95.0%, and 93.0%, respectively. CONCLUSIONS: In patients with initial diagnosis of intermediate- and high-risk prostate cancer, 68Ga-PSMA I&T PET/CT emerges as a relevant staging procedure by identifying nodal and/or distant metastases. Due to the low prevalence of extraprostatic disease, its value seems to be limited in low-risk disease.

Comparison of 68 Ga-PSMA ligand PET/CT versus conventional cross-sectional imaging for target volume delineation for metastasis-directed radiotherapy for metachronous lymph node metastases from prostate cancer.

PURPOSE: To assess the differences in the target volume (TV) delineation of metachronous lymph node metastases between 68 Ga-PSMA ligand PET/CT and conventional imaging in a comparative retrospective contouring study. PATIENTS AND METHODS: Twenty-five patients with biochemical prostate cancer recurrence after primary prostatectomy underwent 68 Ga-PSMA ligand PET/CT in addition to conventional imaging techniques such as CT and/or MR imaging for restaging. All patients were diagnosed with at least one lymph node metastasis. TVs were manually delineated in two different ways: (a) based on conventional imaging (CT/MRI) and (b) based on conventional imaging (CT/MRI) plus 68 Ga-PSMA ligand PET/CT. The size of TVs, overlap rates, and subjective assessment of the difficulty of TV delineation reported by the radiation oncologist (easy/moderate/difficult) were compared. RESULTS: With the additional information from PSMA ligand PET, 47 lymph node metastases were identified and included in the gross tumor volume (GTV). The median clinical target volume (CTV) of non-PET-based TV delineation was statistically larger than the CTV based on PET imaging (134.8 ml [range 6.9-565.2] versus 44.9 ml [range 4.9-481.3; p = 0.001]). The CTV based on CT/MRI enclosed only 81.3% (39/48) of PET-positive lymph nodes. The CT/MRI-based CTV did not enclose all PET-positive lymph nodes in 24% (6/25) of patients. In 12% (3/25) of patients, all PET-positive lymph nodes were outside of the CT/MRI-based CTV. The median overlap rates (TVPET/TVCT/MRIâ€¯× 100) were 45.7% (range 0-96.9) for the GTV and 71.7% (range 9.8-98.2) for the CTV. The assessment of difficulty of contouring revealed that contouring with the additional imaging information of the PET was categorized as easy/moderate in 92% (23/25) and as difficult in 8% (2/25) of the cases, whereas contouring based on CT/MRI without PET was categorized as difficult in 56% (14/25) and as easy/moderate in 44% of the cases (11/25; p = 0.003). CONCLUSION: 68 Ga-PSMA ligand PET/CT is superior to conventional cross-sectional imaging for the delineation of lymph node metastases from prostate cancer. PET-based TV delineation allows for smaller target volumes and should be considered the standard for irradiation of metachronous lymph node metastases in recurrent prostate cancer. Conventional imaging is not sufficiently sensitive for radio-oncological treatment concepts in oligometastatic prostate cancer.

EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (177Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.

Consensus on molecular imaging and theranostics in prostate cancer.

Rapid developments in imaging and treatment with radiopharmaceuticals targeting prostate cancer pose issues for the development of guidelines for their appropriate use. To tackle this problem, international experts representing medical oncologists, urologists, radiation oncologists, radiologists, and nuclear medicine specialists convened at the European Association of Nuclear Medicine Focus 1 meeting to deliver a balanced perspective on available data and clinical experience of imaging in prostate cancer, which had been supported by a systematic review of the literature and a modified Delphi process. Relevant conclusions included the following: diphosphonate bone scanning and contrast-enhanced CT are mentioned but rarely recommended for most patients in clinical guidelines; MRI (whole-body or multiparametric) and prostate cancer-targeted PET are frequently suggested, but the specific contexts in which these methods affect practice are not established; sodium fluoride-18 for PET-CT bone scanning is not widely advocated, whereas gallium-68 or fluorine-18 prostate-specific membrane antigen gain acceptance; and, palliative treatment with bone targeting radiopharmaceuticals (rhenium-186, samarium-153, or strontium-89) have largely been replaced by radium-223 on the basis of the survival benefit that was reported in prospective trials, and by other systemic therapies with proven survival benefits. Although the advances in MRI and PET-CT have improved the accuracy of imaging, the effects of these new methods on clinical outcomes remains to be established. Improved communication between imagers and clinicians and more multidisciplinary input in clinical trial design are essential to encourage imaging insights into clinical decision making.

Targeting Chemokine Receptor CXCR4 and Translocator Protein for Characterization of High-Risk Plaque in Carotid Stenosis Ex Vivo.

Background and Purpose- This pilot study aims to demonstrate the feasibility of targeting molecular characteristics of high-risk atherosclerotic plaque in symptomatic and asymptomatic carotid stenosis (CS), that is, upregulation of the translocator protein (TSPO) and the chemokine receptor type 4 (CXCR4), by means of molecular imaging. Methods- In a translational setting, specimens of carotid plaques of patients with symptomatic and asymptomatic CS obtained by carotid endarterectomy were analyzed for the presence of TSPO and CXCR4 by autoradiography, using the positron emission tomography tracers 18F-GE180 and 68Ga-Pentixafor and evaluated by histopathology. In addition, 68Ga-Pentixafor positron emission tomography/computed tomography was performed in a patient with high-grade CS. Results- Distinct patterns of upregulation of TSPO (18F-GE180 uptake) and CXCR4 (68Ga-Pentixafor uptake) were identified in carotid plaque by autoradiography. The spatial distribution was associated with specific histological hallmarks that are established features of high-risk plaque: TSPO upregulation correlated with activated macrophages infiltration, whereas CXCR4 upregulation also corresponded to areas of intraplaque hemorrhage. 68Ga-Pentixafor uptake was significantly higher in plaques of symptomatic compared with asymptomatic CS. Clinical positron emission tomography revealed marked 68Ga-Pentixafor uptake in carotid plaque of a patient with high-grade CS. Conclusions- Clinical imaging of molecular signatures of high-risk atherosclerotic plaque is feasible and may become a promising diagnostic tool for comprehensive characterization of carotid disease. This methodology provides a platform for future studies targeting carotid plaque.

Patterns of relapse as determined by 68Ga-PSMA ligand PET/CT after radical prostatectomy : Importance for tailoring and individualizing treatment.

PURPOSE: To evaluate the patterns of relapse and impact on the intended treatment when using 68Ga-prostate-specific membrane antigen (PSMA) ligand positron emission tomography/computed tomography (PET/CT) imaging for restaging of disease in patients with biochemical relapse after radical prostatectomy (RP) before salvage radiotherapy (sRT). METHODS: In all, 39 patients with biochemical recurrence after RP who had no primary indication for adjuvant RT due to the absence of biologically unfavorable disease (e.g., extracapsular extension, seminal vesicle invasion, positive margins, or lymph node involvement) underwent a 68Ga-PSMA ligand PET/CT for planning of sRT. RESULTS: PET/CT was positive in 84.6% (33/39) of patients. A total of 61 lesions were observed in these patients (on average 1.8 lesions per patient); 30.3% (10/33) of patients had locally recurrent disease in the prostatic bed. The clinical TNM stage (TNM: tumour-lymph nodes-metastasis-classification) was altered in 69.7% (23/33) of patients following PET, resulting in individualized treatment concepts. A prostate-specific antigen (PSA) >1.0 ng/mL was significantly associated with an increased risk of extrapelvic metastatic disease (p = 0.048). The PSA level at the time of PSMA ligand PET/CT correlated with the peak standardized uptake value (SUVpeak; p = 0.002). According to current clinical guidelines, the remaining 15.4% (6/39) of patients without evidence of disease on PET received sRT with a dose of 66.0 Gy. CONCLUSION: Our results suggest that in patients with biochemical recurrence who did not receive early sRT, a 68Ga-PSMA ligand PET/CT for restaging of disease allows for tailoring and individualizing treatment. Particularly in patients with PSA levels above 1.0 ng/mL, a 68Ga-PSMA ligand PET/CT should be performed for therapy planning, since patients often have metastases not confined to the pelvis.

Imaging of chemokine receptor CXCR4 expression in culprit and nonculprit coronary atherosclerotic plaque using motion-corrected [68Ga]pentixafor PET/CT.

PURPOSE: The chemokine receptor CXCR4 is a promising target for molecular imaging of CXCR4+ cell types, e.g. inflammatory cells, in cardiovascular diseases. We speculated that a specific CXCR4 ligand, [68Ga]pentixafor, along with novel techniques for motion correction, would facilitate the in vivo characterization of CXCR4 expression in small culprit and nonculprit coronary atherosclerotic lesions after acute myocardial infarction by motion-corrected targeted PET/CT. METHODS: CXCR4 expression was analysed ex vivo in separately obtained arterial wall specimens. [68Ga]Pentixafor PET/CT was performed in 37 patients after stent-based reperfusion for a first acute ST-segment elevation myocardial infarction. List-mode PET data were reconstructed to five different datasets using cardiac and/or respiratory gating. Guided by CT for localization, the PET signals of culprit and various groups of nonculprit coronary lesions were analysed and compared. RESULTS: Ex vivo, CXCR4 was upregulated in atherosclerotic lesions, and mainly colocalized with CD68+ inflammatory cells. In vivo, elevated CXCR4 expression was detected in culprit and nonculprit lesions, and the strongest CXCR4 PET signal (median SUVmax 1.96; interquartile range, IQR, 1.55-2.31) was observed in culprit coronary artery lesions. Stented nonculprit lesions (median SUVmax 1.45, IQR 1.23-1.88; P = 0.048) and hot spots in naive remote coronary segments (median SUVmax 1.34, IQR 1.23-1.74; P = 0.0005) showed significantly lower levels of CXCR4 expression. Dual cardiac/respiratory gating provided the strongest CXCR4 PET signal and the highest lesion detectability. CONCLUSION: We demonstrated the basic feasibility of motion-corrected targeted PET/CT imaging of CXCR4 expression in coronary artery lesions, which was triggered by vessel wall inflammation but also by stent-induced injury. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of coronary atherosclerotic plaque.

Dual-Nuclide Radiopharmaceuticals for Positron Emission Tomography Based Dosimetry in Radiotherapy.

Improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual-nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, which are based on common and widely available metal radionuclides. Dual-chelator conjugates, featuring interlinked cyclen- and triazacyclononane-based polyphosphinates DOTPI and TRAP, allow for strictly regioselective complexation of therapeutic (e.g., 177 Lu, 90 Y, or 213 Bi) and PET (e.g., 68 Ga) radiometals in the same molecular framework by exploiting the orthogonal metal ion selectivity of these chelators (DOTPI: large cations, such as lanthanide(III) ions; TRAP: small trivalent ions, such as GaIII ). Such DOTPI-TRAP conjugates were decorated with 3 Gly-urea-Lys (KuE) motifs for targeting prostate-specific membrane antigen (PSMA), employing Cu-catalyzed (CuAAC) as well as strain-promoted (SPAAC) click chemistry. These were labeled with 177 Lu or 213 Bi and 68 Ga and used for in vivo imaging of LNCaP (human prostate carcinoma) tumor xenografts in SCID mice by PET, thus proving practical applicability of the concept.

Molar Activity of Ga-68 Labeled PSMA Inhibitor Conjugates Determines PET Imaging Results.

Radiopharmaceuticals targeting the enzyme prostate-specific membrane antigen (PSMA; synonyms: glutamate carboxypeptidase II, NAALADase; EC 3.4.17.21) have recently emerged as powerful agents for diagnosis and therapy (theranostics) of prostate carcinoma (PCa). The radiation doses for therapeutic application of such compounds are limited by substantial uptakes in kidneys and salivary glands, with excess doses reportedly leading to radiotoxicity-related adverse effects, such as kidney insufficiency or xenostomia. On the basis of the triazacyclononane-triphosphinate (TRAP) chelator, monomeric to trimeric conjugates of the PSMA inhibitor motif lysine-urea-glutamic acid (KuE) were synthesized by means of Cu(I)-mediated (CuAAC) or 5-aza-dibenzocyclooctyne (DBCO)-driven, strain-promoted click chemistry (SPAAC), which were labeled with gallium-68 for application in positron emission tomography (PET), and characterized in terms of PSMA affinity (determined in cellular displacement assays against I-125-BA) and lipophilicity (expressed as log D). Using subcutaneous murine LNCaP (PSMA-positive human prostate carcinoma) xenografts, the influence of ligand multiplicity, affinity, polarity, and molar activity (i.e., mass dose) on the uptakes in tumor, kidney, salivary, and background (muscle) was analyzed by means of region-of-interest (ROI) based quantification of small-animal PET imaging data. As expected, trimerization of the KuE motif resulted in high PSMA affinities (IC50 ranging from 6.0-1.5 nM). Of all parameters, molar activity/cold mass had the most pronounced influence on PET uptakes. Because accumulation in nontumor tissues was effected to a larger extent than tumor uptakes, lower molar activities resulted in substantially better tumor-to-organ ratios. For example, for one trimer, 68Ga-AhxKuE3 (IC50 = 1.5 ± 0.3 nM, log D = -3.8 ± 0.1), a higher overall amount of active compound (12 pmol vs 2 nmol, equivalent to molar activities of 1200 and 8 MBq/nmol) resulted in a remarkable reduction of the kidney-to-tumor ratio from 11.4 to 1.4, respectively, at 60 min p.i. Our study suggests that, for PSMA-targeting radiopharmaceuticals, molar activity has a more pronounced influence on small-animal PET imaging results than structural or in vitro parameters.