Purpose Peptide receptor radionuclide therapy using β-emitting radiolabelled somatostatin analogues like DOTA, Tyr 3 -octreotate shows beneficial results in patients suffering from somatostatin receptor overexpressing tumours. However, after high-dose therapy partial renal reabsorption of radiopeptides may lead to nephrotoxicity. Co-infusion of lysine/arginine lowers renal retention of these radiopeptides without affecting tumour uptake. Recently coadministration of Gelofusine has been described to have a comparable kidney-protecting effect in rats. In the present study optimal dosing of Gelofusine co-administration was studied in tumour-bearing rats. Methods Doses of 40, 80, 120 or 160 mg/kg Gelofusine were co-injected with 15 µg DOTA,Tyr 3 -octreotate, labelled with 3 MBq 111 In for biodistribution (24 h postinjection, n=4 per group) and with 60 MBq 111 In for microSPECT imaging experiments at 3, 24 and 48 h postinjection. An additional group of rats received 80 mg/kg Gelofusine plus 400 mg/kg lysine co-injection. Biodistribution studies were performed both in older (475 g) and younger (300 g) rats, the latter bearing CA20948 tumours. Results Co-injection of 40 mg/kg Gelofusine resulted in 40-50% reduction of renal uptake and retention of 111 In-DOTA,Tyr 3 -octreotate, whereas higher doses further increased the reduction to 50-60% in both groups of rats. Combining Gelofusine and lysine caused 70% reduction of renal uptake. The uptake of radiolabelled octreotate both in somatostatin receptor-expressing normal tissues and tumours was not affected by Gelofusine co-injection. Conclusion In rats co-injection of 80 mg/kg Gelofusine resulted in maximum reduction of renal retention of 111 In-DOTA,Tyr 3 -octreotate, which was further improved when combined with lysine. Tumour uptake of radiolabelled octreotate was not affected, resulting in an increased tumour to kidney ratio.

High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with b-particle-emitting radiolabeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal radiation dose. In rat PRRT studies, renal protection by the coadministration of lysine was confirmed by histologic examination of kidney specimens indicating nephrotoxicity. In the current study, we investigated dedicated small-animal SPECT/CT renal imaging in rats to monitor renal function in vivo during follow-up of PRRT, with and without lysine. Methods: The following 3 groups of rats were imaged using a multipinhole SPECT/CT camera: controls (group 1) and rats at more than 90 d after therapy with 460 MBq (15 mg) of 177 Lu-DOTA-Tyr 3 -octreotate without (group 2) or with (group 3) a 400-mg/kg lysine coinjection as kidney protection (n $ 6 per group). At 90 and 140 d after therapy, static kidney scintigraphy was performed at 2 h after injection of 25 MBq of 99m Tc-dimercaptosuccinic acid ( 99m Tc-DMSA). In addition, dynamic dual-isotope renography was performed using 50 MBq of 111 In-diethylenetriaminepentaacetic acid ( 111 In-DTPA) and 50 MBq of 99m Tc-mercaptoacetyltriglycine ( 99m Tc-MAG3) at 100-120 d after therapy. Results: 111 In-DTPA and 99m Tc-MAG3 studies revealed a time-activity pattern comparable to those in patients, with a peak at 2-6 min followed by a decline of renal radioactivity. Reduced 111 In-DTPA, 99m Tc-MAG3, and 99m Tc-DMSA uptake indicated renal damage in group 2, whereas group 3 showed only a decrease of 99m Tc-MAG3 peak activity. These results indicating nephrotoxicity in group 2 and renal protection in group 3 correlated with levels of urinary protein and serum creatinine and urea and were confirmed by renal histology. Conclusion: Quantitative dynamic dual-isotope imaging using both 111 In-DTPA and 99m Tc-MAG3 and static 99m Tc-DMSA imaging in rats is feasible using small-animal SPECT, enabling longitudinal monitoring of renal function. 99m Tc-MAG3 renography, especially, appears to be a more sensitive marker of tubular function after PRRT than serum chemistry or 99m Tc-DMSA scintigraphy.

The combined α-, γ-, and x-ray emitter 213 Bi (half-life, 46 min) is promising for radionuclide therapy. SPECT imaging of 213 Bi is challenging, because most emitted photons have a much higher energy (440 keV) than common in SPECT. We assessed 213 Bi imaging capabilities of the Versatile Emission Computed Tomograph (VECTor) dedicated to (simultaneous) preclinical imaging of both SPECT and PET isotopes over a wide photon energy range of 25-600 keV. Methods: VECTor was equipped with a dedicated clustered pinhole collimator. Both the 79 keV x-rays and the 440 keV γ-rays emitted by 213 Bi could be imaged. Phantom experiments were performed to determine the maximum resolution, contrast-to-noise ratio, and activity recovery coefficient for different energy window settings. Additionally, imaging of [ 213 Bi-DOTA,Tyr 3 ]octreotate and 213 Bi-diethylene triamine pentaacetic acid (DTPA) in mouse models was performed. Results: Using 440 keV γ-rays instead of 79 keV x-rays in image reconstruction strongly improved the resolution (0.75 mm) and contrast-to-noise characteristics. Results obtained with a single 440 keV energy window setting were close to those with a combined 79 keV/440 keV window. We found a reliable activity recovery coefficient down to 0.240 MBq/mL with 30-min imaging time. In a tumor-bearing mouse injected with 3 MBq of [ 213 Bi-DOTA,Tyr 3 ]octreotate, tumor uptake could be visualized with a 1-h postmortem scan. Imaging a nontumor mouse at 5-min frames after injection of 7.4 MBq of 213 Bi-DTPA showed renal uptake and urinary clearance, visualizing the renal excretion pathway from cortex to ureter. Quantification of the uptake data allowed kinetic modeling and estimation of the absorbed dose to the kidneys. Conclusion: It is feasible to image 213 Bi down to a 0.75-mm resolution using a SPECT system equipped with a dedicated collimator. Newoppor tunities for high linear energy transfer radionuclide therapy with the a-particle emitters 225 Ac and 213 Bi are increasingly being investigated (1-3). The research for peptide receptor radionuclide therapy with a-particles is mostly focused on labeling peptides with 213 Bi. Not only is the short half-life of 46 min for 213 Bi in good accordance with the rapid targeting to receptor-positive tumors and the rapid clearance of peptides, it also raises less concern for detrimental effects because of the absence of nonspecific uptake by daughters detached from its peptide or linker due to a-decay recoil (4). 213 Bi offers the best imaging opportunities through its 440 keV g-ray and is therefore important for biodistribution and dosimetry studies (5). All other g-rays and x-rays emitted by 213 Bi and its daughters are too low either in abundance or in energy to be suitable for imaging, possibly with the exception of the x-rays from 213 Bi at 77 and 79 keV if appropriate correction methods for down-scatter of the 440 keV g-rays are applied (Supplemental Table 1; supplemental materials are available at http://jnm.snmjournals.org (6)). Patient imaging of the uptake patte...

This review addresses nuclear SPECT and PET imaging in small animals in relation to the atherosclerotic disease process, one of our research topics of interest. Imaging of atherosclerosis in small animal models is challenging, as it operates at the limits of current imaging possibilities regarding sensitivity, and spatial resolution. Several topics are discussed, including technical considerations that apply to image acquisition, reconstruction, and analysis. Moreover, molecules developed for or applied in these small animal nuclear imaging studies are listed, including target-directed molecules, useful for imaging organs or tissues that have elevated expression of the target compared to other tissues, and molecules that serve as substrates for metabolic processes. Differences between animal models and human pathophysiology that should be taken into account during translation from animal to patient as well as differences in tracer behavior in animal vs. man are also described. Finally, we give a future outlook on small animal radionuclide imaging in atherosclerosis, followed by recommendations. The challenges and solutions described might be applicable to other research fields of health and disease as well.