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Purpose: RGD peptide-based radiotracers are well established as integrin αβ imaging probes to evaluate tumor angiogenesis or tissue remodeling after ischemia or infarction. In order to optimize the labeling process and pharmacokinetics of the imaging probes, we synthesized three dimeric RGD peptides with or without PEGylation and performed in vivo screening. Procedures: Radiolabeling was achieved through the reaction of F-18 aluminum-fluoride complex with the cyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Three imaging probes were synthesized as F-AlF-NOTA-E[c(RGDfK)], F-AlF-NOTA-PEG-E[c(RGDfK)], and F-AlF-NOTA-E[PEG-c(RGDfk)]. The receptor binding affinity was determined by competitive cell binding assay, and the stability was evaluated by mouse serum incubation. Tumor uptake and whole body distribution of the three tracers were compared through direct tissue sampling and PET quantification of U87MG tumor-bearing mice. Results: All three compounds remained intact after 120 min incubation with mouse serum. They all had a rapid and relatively high tracer uptake in U87MG tumors with good target-to-background ratios. Compared with the other two tracers, F-AlF-NOTA-E[PEG-c(RGDfk)] had the highest tumor uptake and the lowest accumulation in the liver. The integrin receptor specificity was confirmed by co-injection of unlabeled dimeric RGD peptide. Conclusion: The rapid one-step radiolabeling strategy by the complexation of F-aluminum fluoride with NOTA-peptide conjugates was successfully applied to synthesize three dimeric RGD peptides. Among the three probes developed, F-AlF-NOTA-E[PEG-c(RGDfk)] with relatively low liver uptake and high tumor accumulation appears to be a promising candidate for further translational research. [ABSTRACT FROM AUTHOR]

Purpose: CXCR4 is overexpressed on tumor cells from many types of human cancers. A high level of CXCR4 expression often correlates with poor prognosis, chemotherapy resistance, and metastasis. The development of CXCR4-specific radiotracers for positron emission tomography (PET) imaging will allow in vivo evaluation of receptor expression level for diagnosis or therapeutic evaluation. Procedures: Two new 18F-labeled radiotracers based on an Ac-TC14012 peptide, [ 18F]FP-Ac-TC14012 and [ 18F]FB-Ac-TC14012, were synthesized and characterized. The affinities of the 2-fluoropropionate (FP)-conjugated or 4-fluorobenzoate (FB)-conjugated peptides to CXCR4-transfected Chinese hamster ovarian (CHO) cells were evaluated in a competitive binding assay with [ 125I]CXCL12 radioligand. The cell uptake and retention of [ 18F]FP-labeled and [ 18F]FB-labeled peptides were measured. The tumor targetability and pharmacokinetics of these two tracers were also evaluated by microPET imaging and biodistribution studies. Results: The labeled peptides retained high binding affinity to CXCR4 and showed much higher uptake in CXCR4-positive CHO cells than in CXCR4-negative cells in vitro. The smaller and more hydrophilic [ 18F]FP prosthetic group resulted in higher affinity and lower nonspecific cell uptake compared to the [ 18F]FB-labeled peptide. Both radiotracers showed much higher accumulation in CXCR4-positive than CXCR4-negative tumor xenografts in mice and allowed clear visualization of CXCR4 expression by PET. Among the two, [ 18F]FP-Ac-TC14012 showed higher tumor uptake and better tumor-to-background contrast. Unlike their N-terminal 4- F-benzoate analogs, these two tracers had minimal blood retention, likely due to reduced red blood cell binding. Metabolic organs, such as the liver and kidney, also showed high uptake. When blocked with low-dose cold peptide (10 μg), the tumor uptake was significantly increased, most likely due to the increased concentration in blood circulation, as evidenced by decreased liver uptake. Conclusion: These results demonstrate that the [ 18F]FP-labeled Ac-TC14012 peptide with high tumor uptake, low nonspecific binding, and good tumor-to-background contrast promises [ 18F]FP-Ac-TC14012 as a PET tracer for in vivo PET imaging of CXCR4 expression. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the application of the three-compartment restriction spectrum imaging (RSI) model, diffusion kurtosis imaging (DKI), and diffusion-weighted imaging (DWI) in predicting Ki-67 status in rectal carcinoma., Methods: A total of 80 rectal carcinoma patients, including 47 high-proliferation (Ki-67 > 50%) cases and 33 low-proliferation (Ki-67 ≤ 50%) cases, underwent pelvic MRI were enrolled. Parameters derived from RSI (f 1 , f 2 , and f 3 ), DKI (MD and MK), and DWI (ADC) were calculated and compared between the two groups. Logistic regression (LR) analysis was conducted to identify independent predictors and assess combined diagnosis. Area under the receiver operating characteristic curve (AUC), DeLong analysis, and calibration curve analyses were performed to evaluate diagnostic performance., Results: The patients with high-proliferation rectal carcinoma exhibited significantly higher f 1 and MK values and significantly lower ADC, MD, f 2 , and f 3 values than those with low-proliferation rectal carcinoma (P < 0.05). LR analysis showed that MD, MK, and f 2 were independent predictors for Ki-67 status in rectal carcinoma. Moreover, the combination of these three parameters achieved an optimal diagnostic efficacy (AUC = 0.877, sensitivity = 80.85%, specificity = 84.85%) that was significantly better than that obtained using ADC (AUC = 0.783, Z = 2.347, P = 0.019), f 2 (AUC = 0.732, Z = 2.762, P = 0.006), and f 3 (AUC = 0.700, Z = 3.071, P = 0.002). The combined diagnosis also showed good performance (AUC = 0.859) in the internal validation analysis based on 1000 bootstrap samples, while the calibration curve demonstrated that the combined diagnosis provided good stability., Conclusion: RSI, DKI, and DWI can effectively differentiate between patients with high- and low-proliferation rectal carcinoma. Furthermore, the MD, MK, and f 2 imaging parameters may be a novel and promising combination biomarker for examining Ki-67 status in rectal carcinoma., Competing Interests: Declaration of Competing Interest All authors declare no relationships with any companies whose products or services may be related to the subject matter of the article., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Unlabelled: A single dynamic PET acquisition using multiple tracers administered closely in time could provide valuable complementary information about a tumor's status under quasiconstant conditions. This study aimed to investigate the utility of dual-tracer dynamic PET imaging with (18)F-alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) and (18)F-FDG for parametric monitoring of tumor responses to therapy., Methods: We administered doxorubicin to one group of athymic nude mice with U87MG tumors and paclitaxel protein-bound particles to another group of mice with MDA-MB-435 tumors. To monitor therapeutic responses, we performed dual-tracer dynamic imaging, in sessions that lasted 90 min, starting with injection via the tail vein catheters with (18)F-alfatide II, followed 40 min later by (18)F-FDG. To achieve signal separation of the 2 tracers, we fit a 3-compartment reversible model to the time-activity curve of (18)F-alfatide II for the 40 min before (18)F-FDG injection and then extrapolated to 90 min. The (18)F-FDG tumor time-activity curve was isolated from the 90-min dual-tracer tumor time-activity curve by subtracting the fitted (18)F-alfatide II tumor time-activity curve. With separated tumor time-activity curves, the (18)F-alfatide II binding potential (Bp = k3/k4) and volume of distribution (VD) and (18)F-FDG influx rate ((K1 × k3)/(k2 + k3)) based on the Patlak method were calculated to validate the signal recovery in a comparison with 60-min single-tracer imaging and to monitor therapeutic response., Results: The transport and binding rate parameters K1-k3 of (18)F-alfatide II, calculated from the first 40 min of the dual-tracer dynamic scan, as well as Bp and VD correlated well with the parameters from the 60-min single-tracer scan (R(2) > 0.95). Compared with the results of single-tracer PET imaging, (18)F-FDG tumor uptake and influx were recovered well from dual-tracer imaging. On doxorubicin treatment, whereas no significant changes in static tracer uptake values of (18)F-alfatide II or (18)F-FDG were observed, both (18)F-alfatide II Bp and (18)F-FDG influx from kinetic analysis in tumors showed significant decreases. For therapy of MDA-MB-435 tumors with paclitaxel protein-bound particles, a significant decrease was observed only with (18)F-alfatide II Bp value from kinetic analysis but not (18)F-FDG influx., Conclusion: The parameters fitted with compartmental modeling from the dual-tracer dynamic imaging are consistent with those from single-tracer imaging, substantiating the feasibility of this methodology. Even though no significant differences in tumor size were found until 5 d after doxorubicin treatment started, at day 3 there were already substantial differences in (18)F-alfatide II Bp and (18)F-FDG influx rate. Dual-tracer imaging can measure (18)F-alfatide II Bp value and (18)F-FDG influx simultaneously to evaluate tumor angiogenesis and metabolism. Such changes are known to precede anatomic changes, and thus parametric imaging may offer the promise of early prediction of therapy response.

Arylboronates capture aqueous (18)F-fluoride in one step to afford a highly polar (18)F-labeled aryltrifluoroborate anion ((18)F-ArBF(3) (-)) that clears rapidly in vivo. To date however, there is little data to show that a ligand labeled with a prosthetic (18)F-ArBF(3) (-) will provide functional images. RGD, a high-affinity ligand for integrins that are present on the cell surface of numerous tumors, has been labeled in many formats with many different radionuclides, and as such represents a well-established ligand that can be used to evaluate new labeling methods. Herein we have labeled RGD with a prosthetic (18)F-ArBF(3) (-) via two approaches for the first time: 1) a RGD-boronate bioconjugate is directly labeled in one step and 2) an alkyne-modified arylborimidine is first converted to the corresponding (18)F-ArBF(3) (-) which is then conjugated to an RGD-azide via Cu(+)-mediated [2+3] dipolar cycloaddition in one pot over two steps. RGD-(18)F-ArBF(3) (-) bionconjugates were produced in reasonable radiochemical yields using low amounts of (18)F-fluoride anion (10-50 mCi). Despite relatively low specific activities, good tumor images are revealed in each case.