Effects of isoflurane anaesthesia depth and duration on renal function measured with [99mTc]Tc-mercaptoacetyltriglycine SPECT in mice.

BACKGROUND: The influence of anaesthetic depth and the potential influence of different anaesthetic beds and thus different handling procedures were investigated in 86 severe combined immunodeficient (SCID) mice using semi-stationary dynamic single photon emission computed tomography (SPECT) for kidney scintigraphy. Therefore, isoflurane concentrations were adjusted using respiratory rate for low (80-90 breath/min) and deep anaesthesia (40-45 breath/min). At low anaesthesia, we additionally tested the influence of single bed versus 3-mouse bed hotel; the hotel mice were anaesthetized consecutively at ~ 30, 20, and 10 min before tracer injections for positions 1, 2, and 3, respectively. Intravenous [99mTc]Tc-MAG3 injection of ~ 28 MBq was performed after SPECT start. Time-activity curves were used to calculate time-to-peak (Tmax), T50 (50% clearance) and T25 (75% clearance). RESULTS: Low and deep anaesthesia corresponded to median isoflurane concentrations of 1.3% and 1.5%, respectively, with no significant differences in heart rate (p = 0.74). Low anaesthesia resulted in shorter aortic blood clearance half-life (p = 0.091) and increased relative renal tracer influx rate (p = 0.018). A tendency toward earlier Tmax occurred under low anaesthesia (p = 0.063) with no differences in T50 (p = 0.40) and T25 (p = 0.24). Variance increased with deep anaesthesia. Compared to single mouse scans, hotel mice in position 1 showed a delayed Tmax, T50, and T25 (p < 0.05 each). Furthermore, hotel mice in position 1 showed delayed Tmax versus position 3, and delayed T50 and T25 versus position 2 and 3 (p < 0.05 each). No difference occurred between single bed and positions 2 (p = 1.0) and 3 (p = 1.0). CONCLUSIONS: Deep anaesthesia and prolonged low anaesthesia should be avoided during renal scintigraphy because they result in prolonged blood clearance half-life, delayed renal influx and/or later Tmax. Vice versa, low anaesthesia with high respiratory rates of 80-90 rpm and short duration (≤ 20 min) should be preferred to obtain representative data with low variance.

Monitoring orthodontic tooth movement in rats after piezocision by bone scintigraphy.

AIM: Piezocision, corticocision of mineralized tissue by ultrasound showed promising results in accelerating tooth movement induced by orthodontic appliances although the biologic effects of this procedure are not well-understood so far. The aim of this study was to investigate the impact of piezocision on bone remodeling in rats by bone SPECT imaging. MATERIAL AND METHODS: Ten male Wistar rats underwent surgical placement of orthodontic appliances on each side of the maxilla followed by piezocision on one side only. Each rat underwent 99mTc-MDP bone SPECT/CT imaging before surgery (T0), and 2 (T1) and 4 weeks (T2) after surgery. Bone uptake is expressed as median [IQR] min-max in percentage of the injected activity per ml computed from the 10 voxels with the highest uptake (%IAmax10/ml). RESULTS: Pooled data regardless of the piezocision showed a significant increase in bone uptake from T0 (3.2 [2.8-3.9] 2.6-4.9) to T1 (4.4 [3.8-4.6] 3.4-4.8; p = 0.001). Thereafter, the uptake decreased to T2 (3.8 [3.1-4.4] 2.8-4.8; p = 0.116). No significant differences in bone uptake were found between the maxilla sides without and with piezocision: T1: without (4.3 [3.8-4.5] 3.4-4.8) vs. with (4.5 [3.7-4.6] 3.5-4.7; p=0.285), T2: without (4.0 [3.1-4.5] 2.8-4.8) vs. with (3.7 [3.0-4.4] 2.8-4.8; p=0.062). CONCLUSION: 99mTc-MDP bone SPECT imaging in rats was able to reproduce changes in bone uptake in the maxilla after placement of orthodontic appliances inducing measurable tooth movement. An additional effect of piezocision on bone remodeling in terms of bone uptake was not detectable which is probably due to the pronounced and significant effects induced by the orthodontic appliances per se, which may mask the potential effects of additional piezocision.

Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy.

PURPOSE: Fibroblast activation protein (FAP) is a membrane-bound protease that has limited expression in normal adult tissues but is highly expressed in the tumor microenvironment of many solid cancers. FAP-2286 is a FAP-binding peptide coupled to a radionuclide chelator that is currently being investigated in patients as an imaging and therapeutic agent. The potency, selectivity, and efficacy of FAP-2286 were evaluated in preclinical studies. METHODS: FAP expression analysis was performed by immunohistochemistry and autoradiography on primary human cancer specimens. FAP-2286 was assessed in biochemical and cellular assays and in in vivo imaging and efficacy studies, and was further evaluated against FAPI-46, a small molecule-based FAP-targeting agent. RESULTS: Immunohistochemistry confirmed elevated levels of FAP expression in multiple tumor types including pancreatic, breast, and sarcoma, which correlated with FAP binding by FAP-2286 autoradiography. FAP-2286 and its metal complexes demonstrated high affinity to FAP recombinant protein and cell surface FAP expressed on fibroblasts. Biodistribution studies in mice showed rapid and persistent uptake of 68Ga-FAP-2286, 111In-FAP-2286, and 177Lu-FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues. 177Lu-FAP-2286 exhibited antitumor activity in FAP-expressing HEK293 tumors and sarcoma patient-derived xenografts, with no significant weight loss. In addition, FAP-2286 maintained longer tumor retention and suppression in comparison to FAPI-46. CONCLUSION: In preclinical models, radiolabeled FAP-2286 demonstrated high tumor uptake and retention, as well as potent efficacy in FAP-positive tumors. These results support clinical development of 68Ga-FAP-2286 for imaging and 177Lu-FAP-2286 for therapeutic use in a broad spectrum of FAP-positive tumors.

Nuclear Medicine Imaging Procedures in Oncology.

Nuclear medicine radionuclide imaging is a quantitative imaging modality based on radioisotope-labeled tracers which emit radiation in the form of photons used for image reconstruction. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the two noninvasive tomographic three-dimensional radionuclide imaging procedures for both clinical and preclinical settings. In this review on nuclear medicine imaging procedures in oncology, a variety of standard SPECT and PET tracers including radioiodine, 18Fluorine fluorodeoxyglucose (18F-FDG), and 68Gallium-labeled small proteins like Prostate Specific Membrane Antigen (PSMA) or somatostatin analogues and their application as targeted molecular imaging probes for improved tumor diagnosis and tumor phenotype characterization are described. Absolute and semiquantitative approaches for calculation of tracer uptake in tumors during the course of disease and during treatment allow further insight into tumor biology, and the combination of SPECT and PET with anatomical imaging procedures like computed tomography (CT) or magnetic resonance imaging (MRI) by hybrid SPECT/CT, PET/CT, and PET/MRI scanners provides both anatomical information and tumor functional characterization within one imaging session. With the recent establishment of novel molecular radiolabeled probes for specific tumor diagnosis, prognosis, and treatment monitoring, nuclear medicine has been able to establish itself as a distinct imaging modality with increased sensitivity and specificity.

Relationship of Renal Function in Mice to Strain, Sex and 177Lutetium-Somatostatin Receptor Ligand Treatment.

AIM: Aim of the study was to establish parameters for 99mTc-MAG3 SPECT renal uptake kinetics in healthy SCID mice as a function of mouse strain and sex and to evaluate the feasibility of this method for detecting 177Lu-somatostatin receptor ligand (177Lu-SRL) treatment effects on kidney function. MATERIALS AND METHODS: Dynamic semi-stationary SPECT acquisitions (68 frames, total duration 35 min) was started prior to i. v. injection of 99mTc-MAG3 in 12 female and 12 male SCID mice. Additionally, 6 female SCID mice with neuroendocrine tumors were imaged 1-5 months after 177Lu-SRL (5 DOTATOC, 1 DOTA-JR11) treatment. Kidney function is expressed as maximum time to peak (Tmax), T50 and T25 in minutes (median [interquartile range]). Differences between groups were tested using the Mann-Whitney-U test, and SCID mouse parameters were compared with data for C57BL/6N mice from a recent publication. RESULTS: Significant sex-based differences in Tmax between strains were observed (females: C57BL/6N 1.6 [1.4-1.7], SCID 1.4 [1.3-1.5], p = 0.05; males: C57BL/6N 1.4 [1.3-1.4], SCID 1.6 [1.4-1.7], p = 0.04). In C57BL/6N mice, females showed a later Tmax (p < 0.01) than males. SCID mice showed no difference (p = 0.14). Treated SCID mice showed no significant delay in Tmax (2.0 [1.4-2.7], p = 0.15) but a significant delay in T50 (p = 0.02) and T25 (p = 0.01) compared to healthy untreated mice. CONCLUSION: This study demonstrated significant sex-related differences between SCID and C57BL/6N mouse strains in kidney function. Establishment of normal values for different strains and sexes therefore is important for experimental therapy studies. Renal SPECT imaging with 99mTc-MAG3 was sufficiently sensitive to detect 177Lu-SRL treatment toxic effects on kidney function in SCID mice.