¹⁸F-Alfatide II and ¹⁸F-FDG Dual-Tracer Dynamic PET for Parametric, Early Prediction of Tumor Response to Therapy

Abstract

A single dynamic PET acquisition using multiple tracers administered closely in time could provide valuable complementary information about a tumor’s status under quasi-constant conditions. This study aims to investigate the utility of dual-tracer dynamic PET imaging with 18F-Alfatide II (18F-AlF-NOTA-E[PEG4-c(RGDfk)]2) and 18F-FDG for parametric monitoring of tumor responses to therapy. Methods We administered doxorubicin to one group of athymic nude mice with U87MG tumors and Abraxane 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 by injecting the mice via tail vein catheters with 18F-Alfatide II, followed 40 minutes later by 18F-FDG. To achieve signal separation of the two tracers, we fit a three-compartment reversible model to the time activity curve (TAC) of 18F-Alfatide II for the 40 min prior to 18F-FDG injection, and then extrapolated to 90 min. The 18F-FDG tumor TAC was isolated from the 90 min dual tracer tumor TAC by subtracting the fitted 18F-Alfatide II tumor TAC. With separated tumor TACs, the 18F-Alfatide II binding potential (Bp=k3/k4) and volume of distribution (VD), and 18F-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 18F-Alfatide II, calculated from the first 40 min of dual tracer dynamic scan, as well as Bp and VD, correlated well with the parameters from the 60 min single tracer scan (R2 > 0.95). Compared with the results of single tracer PET imaging, FDG tumor uptake and influx were recovered well from dual tracer imaging. Upon doxorubicin treatment, while no significant changes in static tracer uptake values of 18F-Alfatide II or 18F-FDG were observed, both 18F-Alfatide II Bp and 18F-FDG influx from kinetic analysis in tumors showed significant decreases. For Abraxane therapy of MDA-MB-435 tumors, significant decrease was only observed with 18F-Alfatide II Bp value from kinetic analysis but not 18F-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 days after doxorubicin treatment started, at day 3 there were already substantial differences in 18F-Alfatide II Bp and 18F-FDG influx rate. Dual tracer imaging can measure 18F-Alfatide II Bp value and 18F-FDG influx simultaneously to evaluate tumor angiogenesis and metabolism. Such changes are known to precede anatomical changes, and thus parametric imaging may offer the promise of early prediction of therapy response.

Preclinical Kinetic Analysis of the Caspase-3/7 PET Tracer 18F-C-SNAT: Quantifying the Changes in Blood Flow and Tumor Retention After Chemotherapy

“…However, 18 F-FDG measurements have been shown to be potentially biased by changes in blood flow after antitumor treatment (25)(26)(27) and increased uptake in inflammatory tissue (8,32) and in hypoxic areas of tumors (27,33), leading to false-negatives. Tracer pharmacokinetic modeling has been developed to correct these biases, for example, the delivery rate 18 F-FDG has been shown to correlate better with tumor response to treatment than the standardized uptake value measurement commonly calculated from static PET images (27,34,35). And the kinetics of the SPECT tracer 99m Tc-duramycin were used to examine heart ischemia.…”

Multiplexed imaging for diagnosis and therapy

“…Moreover, the invasiveness of the procedure is often burdensome for patients and clinicians alike, particularly when repeated procedures are required. Multiplexed molecular imaging instead provides a comprehensive, noninvasive view of tumour pathology and anatomy, and enables the rational selection of therapy, as well as insight into the optimal dosage, early-response assessment and subsequent treatment planning 143,208,[218][219][220] . For example, multiplexed PET in the early-response assessment of mice to VEGF 121 /rGel therapy in a breast-cancer model 220 Ga-DOTA-peptide, and the development of cyclotron-generated 18 F-analogues (e.g., FET-AG-TOCA) for wide patient coverage, underscores the potential role of PET in therapy selection and in the evaluation of potential responses to somatostatin-receptortargeted chemotherapies [221][222][223][224][225] (Fig.…”

Comparing the Diagnostic Potential of 68Ga-Alfatide II and 18F-FDG in Differentiating Between Non–Small Cell Lung Cancer and Tuberculosis

“…Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancer cases (2). 18 F-FDG PET/CT has been well established as a crucial tool for detecting, identifying, and staging NSCLC, with obvious superiority compared with traditional anatomy imaging modalities (2). An SUV greater than 2.5 has been widely accepted as a cutoff value for differentiating lung malignancies from benign cases with 18 F-FDG (3,4).…”

“…18 F-FDG PET/CT has been well established as a crucial tool for detecting, identifying, and staging NSCLC, with obvious superiority compared with traditional anatomy imaging modalities (2). An SUV greater than 2.5 has been widely accepted as a cutoff value for differentiating lung malignancies from benign cases with 18 F-FDG (3,4). However, the specificity of 18 F-FDG PET/CT has been vigorously challenged.…”

“…An SUV greater than 2.5 has been widely accepted as a cutoff value for differentiating lung malignancies from benign cases with 18 F-FDG (3,4). However, the specificity of 18 F-FDG PET/CT has been vigorously challenged. In clinical practice, it is not rare for benign lesions to represent an SUV higher than 2.5 and result in false-positive diagnoses (5).…”