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Semin Nucl Med
2023 Jul 10; doi: 10.1053/j.semnuclmed.2023.06.006.
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Special Challenges in PET Imaging of Ectothermic Vertebrates.
Alstrup AKO
,
Busk M
,
Dittrich A
,
Hansen K
,
Wang T
,
Damkjær M
,
Andersen JB
,
Lauridsen H
.
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The bulk of biomedical positron emission tomography (PET)-scanning experiments are performed on mammals (ie, rodents, pigs, and dogs), and the technique is only infrequently applied to answer research questions in ectothermic vertebrates such as fish, amphibians, and reptiles. Nevertheless, many unique and interesting physiological characteristics in these ectothermic vertebrates could be addressed in detail through PET. The low metabolic rate of ectothermic animals, however, may compromise the validity of physiological and biochemical parameters derived from the images created by PET and other scanning modalities. Here, we review some of the considerations that should be taken into account when PET scanning fish, amphibians, and reptiles. We present specific results from our own experiments, many of which remain previously unpublished, and we draw on examples from the literature. We conclude that knowledge on the natural history and physiology of the species studied and an understanding of the limitations of the PET scanning techniques are necessary to avoid the design of faulty experiments and erroneous conclusions.
Figure 1. Standard metabolic rate (SMR) over body mass across five classes of vertebrates. When normalizing SMR to a body temperature of 38°C using the temperature coefficient, Q10, for ectothermic fish, amphibians and reptiles and comparing to endothermic vertebrates, mammals and birds, it is possible to reveal a general trend that SMR is generally 5- to 10-fold lower in ectotherms compared to similar sized endotherms. The figure is used with permission of The Royal Society, from The scaling and temperature dependence of vertebrate metabolism, White CR, Phillips NF, Seymour RS, Biol. Lett. 2, 125–127 (2006), year of copyright 2005, permission conveyed through Copyright Clearance Center, Inc (Order License ID 1365318-1).
Figure 2. The temperature, the anesthetic of choice, and the medium during scanning is important in aquatic ectotherms. (A) Immersion based anesthetics such as propofol, MS-222 and benzocaine which are often used to induce global anesthesia in aquatic ectotherms affect general metabolism and cardiovascular function. Both propofol, MS-222 and benzocaine reduce oxygen consumption in the axolotl relative to baseline, but whereas propofol induces a small decrease in heart rate, both MS-222 and benzocaine induces tachycardia. (B) Ambient temperature affects blood glucose level and the activity of axolotls. Axolotls are usually housed at 20˚C, and a lowered housing temperature results in a decreased level of blood glucose and less active animals, whereas an increase in housing temperature has the opposite effects. (C) Since it is difficult (but possible) to conduct PET imaging on submerged animals, aquatic ectotherms like the axolotl may in some cases be scanned in air, in which cases the animals should be kept moist and some effect of gill collapse must be expected
Figure 3. Temperature affects specific uptake of PET tracer in the axolotl. (A) Magnetic resonance images (left) and standardized uptake value (SUV) images of 3 axolotls receiving equivalent doses of [18F]FDG (∼0.5 MBq/g) via intravenous injection and imaged with PET after 3 hours at either 10, 20, or 30˚C. Coronal slice at the level of the cardiac ventricle. (B) Like A but coronal slice at the level of the brain, eyes, and gills. The radioactive glucose analog is more specifically taken up by the cardiac ventricle at higher temperatures which indicates increased glycolytic activity of the heart relative to the rest of the body at increasing temperatures.
Figure 4. [18F]FDG biodistribution after 2 hours circulation time in a red-eared slider. [18F]FDG biodistribution determined in an adult red-eared slider (Trachemys scripta elegans) at 20˚C. [18F]FDG (42 MBq) was administered via a venous catheter and blood samples were collected at various time points. After 2 hours the turtle was sacrificed and various organs were collected, weighed and radioactivity was determined, and expressed relative to a final blood sample. The figure insert shows the time development of the blood signal, expressed relative to the first blood sample drawn 5 minutes after [18F]FDG administration.
Figure 5. [18F]FDG in 2 Bumese pythons (Python molurus) maintained at 30˚C. [18F]FDG (42 MBq) was administered via a venous catheter in the tail while the animals were awake. After 2 to 3 hours, the snakes were sedated by a vascular infusion of barbiturates and the PET CT images were obtained immediately thereafter.
Figure 6. A red eared slider (Trachemys scripta sp.) PET-scanned with [15O]H2O to investigate blood perfusion of the shell. (A) Axial, (B) sagittal, and (C) coronal views of the animal display only activity in venous compartments and the heart during 4 minutes following administration of a 2.5 mL bolus of the tracer (500 MBq) in a pentobarbital anaesthetized animal on 1300 g at 21˚C. (D) Photo displaying the inside of the carapace (shell) in another animal (body mass 700 g) following postmortem injection of a computed tomography contrast agent (250 mg/mL BaSO4 mixed with gelatin to ensure curing) and careful dissection. Notice how smaller vessels enter the carapace (arrows), which indicates that the lack of tracer signal from vessels in the shell (and other organs) could be due to signal decay (2.03 minutes half-life for [15O] instead of a complete lack of blood vessels and possibly perfusion. This example showcases the importance of carefully selecting tracers which match the physiological properties of parameters sought assessed in an ectothermic vertebrate that has a much low metabolic rate compared to similar sized mammals. Abbreviations used in (A-C): H, heart; L, lungs; Li, liver; T, trachea; V, venous vessel compartments.
Figure 7. Intraperitoneal tracer injection in an axolotl. (A) Magnetic resonance image (left) and standardized uptake value (SUV) image (middle: with narrow range; right: with wide range) 3 hours postintraperitoneal [18F]FDG (∼1 MBq/g) injection in an axolotl. (B) Similar to A but 5 hours after injection. At both time points, very little tracer substance has left the peritoneal cavity and entered the blood stream or metabolically active organs. Thus within the operating time of 18F as a PET tracer, intraperitoneal injections are not useful.
Figure 8. Autoradiography images of sectioned axolotl heart. Following the injection of 2 radiotracers, [18F]FDG and 14C-acetate, in an axolotl and 2 hours circulation time, the animal was sacrificed and the heart was excised and cryosectioned. By administration of a high dose of [18F]FDG and a low dose of 14C-acetate, and exploiting the widely different half-lives of the two radioisotopes (T1/218F=109.8 min, T1/2(14C)=5730 years), it is feasible to separate the signal from the two tracers, where the first image captured immediately after cryosectioning mainly is due to retention of the glucose analogue and a later image obtained after full decay of [18F]FDG reflects uptake of 14C-acetate. Accordingly, we were able to extract information that relates to glycolytic activity and acetate metabolism in the same animal and tissue section.