KR102692580B1 - A methods for determining optimal dosage of radioactivity for positron emission tomography against non-human primates - Google Patents

Abstract

The present invention relates to a method of determining the optimal amount of radioactivity injected into a primate when performing positron emission tomography, where the loss of radioactivity confirmed in the results of positron emission tomography using a primate organ phantom is below a certain level. Regarding the radiation dose in the case, the optimal radiation dose for positron emission tomography of primates is determined by evaluating whether the quality of the positron emission tomography image meets the NEMA (National Electrical Manufacturers Association) standard using a QC (Quality Control) phantom. Provides a decision method. According to the determination method of the present invention, it is possible to obtain excellent quality positron emission tomography images while exposing primates, such as monkeys, to only minimal radiation. Therefore, even if positron emission tomography is repeatedly performed on the same individual, the pericarp is immune to radiation. Since radiation exposure can be prevented, longitudinal research can be conducted on the same subject without worrying about side effects due to excessive radiation exposure, and radiation exposure to researchers can also be greatly reduced.

Description

{A methods for determining optimal dosage of radioactivity for positron emission tomography against non-human primates}

The present invention relates to a method for determining the optimal radiation dose to be injected into a primate when performing positron emission tomography.

Positron emission tomography (PET) is a test method that obtains the distribution of radiopharmaceuticals through functional cross-sectional imaging. Specifically, a radioactive isotope that emits positrons is bound to a drug, injected into the body of an individual, and then the injected radioactive substance is detected. This is a technology that acquires a three-dimensional tomographic image of the inside of the body by detecting a pair of gamma rays generated through the collision of a material's positron and neighboring electrons and tracking the detection location of the gamma rays.

Unlike computed tomography (CT) and magnetic resonance imaging (MRI), positron emission tomography can provide functional images (presence or absence of tumors) of human organs rather than anatomical images. In particular, it is an essential test item for diagnosing or analyzing brain diseases such as brain tumors, Parkinson's disease, Alzheimer's disease, etc. However, unlike computed tomography, which causes external radiation exposure, positron emission tomography is used due to radioactive pharmaceuticals injected into the body. It may cause internal radiation exposure to the subject receiving the treatment. Therefore, when performing positron emission tomography, it is very important to accurately evaluate and minimize the amount of internal radiation an individual receives in order to reduce unnecessary radiation exposure to the individual and secondary side effects caused by radiation.

Meanwhile, in recent years, preclinical research using positron emission tomography on experimental animals has been increasing. In particular, in the case of non-human primates such as monkeys, although they are the mammals most similar to humans, repeat experiments are not easy compared to small animals such as mice, rats, and rabbits in terms of cost and handling, so non-invasive functional analysis of organs is possible. Positron emission tomography is a very important research method. However, even in the case of non-human primates, there may be problems such as internal radiation exposure and secondary side effects as described above, so it is important to minimize excessive radiation exposure in order to conduct accurate longitudinal studies in the same individual. do. Nevertheless, no research or standards have been established for the appropriate amount of radiation for non-human primates that are different in size from humans. Therefore, in previous studies, the amount of radiation injected into the subject was inconsistent or was used to obtain clearer images. Cases of injecting radioactive pharmaceuticals in somewhat excessive amounts were common.

Accordingly, there is still a need to establish a protocol that can obtain excellent quality images with a low radiation dose optimized when performing positron emission tomography on primates.

The purpose of the present invention is to provide a method for determining the optimal amount of radiation injected into a primate when performing positron emission tomography on a primate.

In order to achieve the above object, the present invention includes the steps of injecting radioactive pharmaceuticals into a primate brain phantom and performing positron emission tomography (PET) multiple times with different amounts of radioactivity; Compare the radioactivity amount of the injected radiopharmaceutical with the radioactivity amount confirmed in the results of the positron emission tomography to select cases where the difference is within 25%, and in the selected cases, the minimum value of the radioactivity amount of the injected radiopharmaceutical and determining the maximum value; varying the amount of radioactivity within the range of the minimum and maximum values, injecting radioactive pharmaceuticals into a quality control (QC) phantom, and performing positron emission tomography multiple times; Confirming at least one image quality-related parameter from the results of positron emission tomography for the QC phantom; And selecting cases where the confirmed image quality-related parameters meet NEMA (National Electrical Manufacturers Association) standards, and confirming the minimum and maximum values of the radioactivity amount of the injected radiopharmaceutical in the selected cases. , provides a method for determining the optimal radiation dose for positron emission tomography of primates.

According to the present invention, it is possible to obtain excellent quality positron emission tomography images while exposing primates such as monkeys to only minimal radiation. Even if positron emission tomography is performed repeatedly on the same individual, excessive exposure to radiation is avoided. This not only makes it possible to conduct longitudinal research on the same subject without worrying about side effects due to excessive radiation exposure, but also significantly reduces radiation exposure to researchers.

However, the effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the following description.

Figure 1 is a cross-sectional view and photograph of a monkey brain phantom manufactured and used in an embodiment of the present invention.
Figure 2 shows the results of an experiment in which 250 MBq of radiopharmaceuticals were injected into a monkey brain phantom and positron emission tomography was performed over time to confirm the loss of radioactivity according to the radioactivity of the actually injected radiopharmaceuticals.
Figure 3 is an image obtained by injecting 20 MBq, 47.8 MBq, and 153.4 MBq of radiopharmaceuticals into the NEMA NU-4 phantom, a QC phantom, and performing positron emission tomography.
Figure 4 is a schematic diagram of a head fixation device used to perform positron emission tomography on monkeys in an embodiment of the present invention and a photograph of the device actually applied to positron emission tomography.
Figures 5a and 5b are images showing the results of analyzing the brain intake of radiopharmaceuticals by performing positron emission tomography by injecting 47.8 MBq and 153.4 MBq of radiopharmaceuticals into the brain of a monkey.

Hereinafter, the present invention will be described in detail.

The present invention provides a method for determining the optimal radiation dose for performing positron emission tomography (PET) on primates.

The primate may be non-human, such as a monkey, orangutan, gorilla, chimpanzee, etc., and may especially be a monkey.

The positron emission tomography is a test method for obtaining functional cross-sectional images of the distribution of radiopharmaceuticals. The positron emission tomography device includes a module capable of detecting pair-annihilation gamma rays emitted from positrons, and the module converts gamma rays into low-energy photons. It consists of a scintillation crystal that converts low-energy photons into electrical signals and amplifies them, and a coincidence circuit that distinguishes simultaneous signals. And the signal detected by the positron emission tomography device is transmitted to a terminal (workstation) and stored as a sinogram.

The optimal radiation dose may be the minimum radiation dose of a radiopharmaceutical that can obtain a positron emission tomography image that complies with NEMA (National Electrical Manufacturers Association) standards.

In the method of determining the optimal radioactivity for positron emission tomography of primates of the present invention, first, the radioactivity is varied, a radiopharmaceutical is injected into a primate organ phantom, and positron emission tomography (PET) is performed. It includes a first step of performing the process multiple times. The first step is a step of collecting information about the amount of radiation actually injected and the amount of radiation confirmed in the image of positron emission tomography. The amount of radioactivity confirmed in the image of positron emission tomography is inevitably lower than the amount of radioactivity of the radiopharmaceutical actually injected into the object, and this difference is called the loss of radioactivity. And, the degree of loss of this amount of radioactivity varies depending on the amount of radioactivity of the radiopharmaceutical actually injected into the object. Therefore, as in the first step, by injecting radiopharmaceuticals with different radioactivity amounts into the primate organ phantom and repeating positron emission tomography several times, when radiopharmaceuticals with a certain amount of radioactivity are injected, the positron emission tomography Information can be collected from the captured images to determine how much radiation is lost. At this time, the phantom is a model that can be used to evaluate the performance of a positron emission tomography device for primates by simulating the physical properties of primate organs. The primate organ phantom of the present invention varies depending on the type of organ to be analyzed. It could be a primate brain phantom.

Based on the information collected through the first step as described above, the radioactivity amount of the injected radiopharmaceutical is compared with the radioactivity amount confirmed in the results of the positron emission tomography, and cases where the difference is within a certain level are selected. , and a second step of determining the minimum and maximum values of the radioactive dose of the injected radiopharmaceutical in the selected case. As described above, since the degree of loss of radioactivity varies depending on the radioactivity of the radiopharmaceutical injected into the object, the second step is performed so that the loss of radioactivity is within a certain level based on the information collected in the first step. This is the step to select cases and determine the range of expected effective radioactivity for positron emission tomography. In particular, when comparing the radioactivity amount of the injected radiopharmaceutical and the radioactivity amount confirmed in the results of the positron emission tomography, the difference is within 30%, for example, within 25%, within 20%, or within 15%. It is possible to select, and in the cases selected as above, the minimum and maximum values of the radioactivity of the injected radiopharmaceutical can be derived to determine the range of the expected effective radioactivity.

Then, the radiation dose is varied within the range of the minimum and maximum values derived as above, and the process of injecting radioactive pharmaceuticals into the phantom for QC (quality control) and performing positron emission tomography is performed multiple times. Includes steps. The third step is a step of collecting image-related information obtained when radiopharmaceuticals are injected with a radioactivity within the range determined in the second step and positron emission tomography is performed. Positron emission tomography is performed using a QC phantom. Perform. The QC phantom is a phantom designed according to recommendations by NEMA to standardize the evaluation of the performance of the positron emission tomography device, and the QC phantom may be a NEMA phantom, NEMA NU-4 phantom, etc. Since the above QC phantom is used, the image-related information obtained in the third step may be standardized, and thus a more objective evaluation of the image quality may be possible.

In addition, it includes a fourth step of confirming at least one image quality-related parameter from the results of positron emission tomography obtained using the QC phantom as described above. The fourth step is a step of checking image quality-related parameters among the image-related information collected in the third step. The image quality-related parameters may be recovery coefficient, uniformity, spill-over ratio, etc. The recovery coefficient compares the amount of radioactivity observed in the actual image to the scanned amount, the uniformity evaluates whether the radioactivity is uniformly distributed in the area of interest, and the spillover ratio measures the degree of radioactive contamination passed from another medium to the medium of interest. It means.

In addition, a fifth step is included to select cases in which the confirmed image quality-related parameters meet NEMA standards and to confirm the minimum and maximum values of the radioactivity of the injected radiopharmaceutical in the selected cases. Since it may not be possible to obtain images with a significant level of quality in the entire range of the expected effective radioactivity derived in the second step, the fifth step is performed among the expected effective radioactivity amounts in which the loss of radioactivity is below a certain level. This is the step to determine the range of radiation dose that can obtain images with a meaningful level of quality. To this end, in the fifth step, cases are selected where at least one of the image quality-related parameters identified in the fourth step meets the NEMA standard, and the radioactivity amount of the injected radiopharmaceutical in the selected cases is selected. By deriving the minimum and maximum values of , the range of optimal radiation dose can be determined. At this time, if the image quality-related parameters confirmed in the fourth step meet the NEMA standard, i) if the recovery coefficient is in the range of 0.75 to 1.25, ii) if the uniformity is 15.0% or less, and iii) in water or air. This means at least one of the cases where the spillover ratio is 15% or less, and in particular, it may satisfy all of the above i) to iii).

Through the first to fifth steps, in the present invention, it is possible to determine the range of the optimal radiation dose that can obtain excellent image quality while reducing the loss of radiation dose, and the minimum radiation dose range among the ranges of optimal radiation dose obtained as described above can be determined. By using only the radioactivity of , it is possible to minimize radiation exposure to primates during research that repeatedly performs positron emission tomography.

Hereinafter, the present invention will be described in detail through examples.

However, the following examples specifically illustrate the present invention, and the content of the present invention is not limited by the following examples.

Preliminary literature search

Through a literature review, the inventors of the present invention investigated the amount of radiation used in conventional studies that performed positron emission tomography on non-human primates such as monkeys.

No. scanner Species Weight (kg) Injection volume (MBq) Injection amount per unit body weight
(MBq/kg) One Focus 220 Cynomolgus 4.3 101.4±42.1 23.6 2 Focus 220 Cynomolgus 6.2 171.0±15.8 27.6 3 Focus 220 Cynomolgus 5.8 169.2±9.0 29.1 4 Focus 220 Rhesus 13.8 179.8±12.8 13.0
(minimum value) 5 Focus 220 Rhesus 12.2 207.0 17.0 6 Focus 220 Rhesus 10.8 222.0±19 20.6 7 Mediso
(LFER 150) Cynomolgus 4.5 90.0 20.0 8 Mediso (Nanoscan) Cynomolgus 2.8 185.0 65.1 9 Mediso (Nanoscan) Cynomolgus 2.9 185.0 64.7 10 SHR-7700 Rhesus 8.0 110.0 13.8 11 SHR-7700 Rhesus 6.4 98.3±13.2 15.4 12 SHR-7700 Rhesus 6.5 510.0 78.5
(maximum value) 13 SHR-17000 Cynomolgus 4.5 244±19 54.2 14 SHR-38000 Rhesus 6.7 150.0 22.4

As a result, as can be seen in Table 1 above, the amount of radioactivity injected into the subject in previous studies was as low as 90 MBq and as high as 244 MBq per subject, and this was confirmed to be inconsistent, ranging from 13 to 78.5 MBq/Kg per body weight. .

From the above results, it can be seen that there is no appropriate radiation dose established to perform positron emission tomography on non-human primates.

Preparation of non-human primate brain phantoms

In order to derive the optimal radiation dose for performing positron emission tomography on non-human primates, a monkey brain phantom capable of simulating the monkey brain was first produced.

The monkey brain phantom was manufactured by 3D printing using urethane to produce an upper and lower plate of the shape shown in Figure 1, and then fitting them together to have a volume of about 80,000 mm ³ .

Deriving the range of expected effective radiation dose using non-human primate brain phantoms

A radiopharmaceutical ( ¹⁸ F-FP-CIT) with a radioactivity of 250 MBq was injected into the monkey brain phantom prepared in Example 2, and positron emission tomography was performed at 20-minute intervals for 10 hours until the radioactivity was 5 MBq. This was performed, and the amount of radiation confirmed in the scanner of the positron emission tomography device was measured. Then, the difference between the radioactivity of the injected radiopharmaceutical and the radioactivity confirmed by the scanner of the positron emission tomography device was compared, and the results are shown in Figure 2.

Among the results in Figure 2, the difference between the radioactivity amount confirmed by the scanner of the positron emission tomography device compared to the radioactivity amount of the injected radiopharmaceutical device, that is, the cases where the loss of radiation dose is 25% or less are selected, and the radiopharmaceuticals injected in these cases are selected. The minimum and maximum values of radioactivity were determined to derive the range of expected effective radioactivity.

As a result, as indicated by gray shading in FIG. 2, it was confirmed that when radiopharmaceuticals were injected with a radioactive amount ranging from 5 MBq to 54.9 MBq, the amount of radioactivity lost was 25% or less, and 5 MBq to 54.9 MBq was the expected effective radioactivity amount. It was decided to be in the range of .

Quality assessment of positron emission tomography images performed within a range of expected effective radioactivity

For the expected effective radiation dose in the range derived in Example 3, positron emission tomography was performed using a QC phantom (NEMA NU-4 phantom), and the quality of the positron emission tomography images obtained therefrom was compared. Specifically, positron emission tomography was performed by injecting radiopharmaceuticals with a low radioactivity of 20 MBq, 47.8 MBq, or a high radioactivity of 153.4 MBq, respectively, into the QC phantom, and the recovery coefficient was calculated for each image taken. (recovery coefficient), uniformity, and spill-over ratio were measured. It was then confirmed whether the three parameters measured in this way complied with the NEMA (National Electrical Manufacturers Association) standards.

As a result, as shown in Tables 2 to 4 below and shown in FIG. 3, a low-radioactivity dose of 20 MBq or 47.8 MBq, which is included in the range of the expected effective radioactivity derived in Example 3, was injected. It was confirmed that even in one case, excellent quality positron emission tomography images meeting NEMA standards could be obtained.

Dose (MBq) RC(recovery coefficient) 1mm 2mm 3mm 4mm 5mm 20 0.12 0.70 1.01 1.08 1.12 47.8 0.10 0.63 1.05 1.15 1.21 153.4 0.37 0.33 0.38 0.57 1.00

Dose (MBq) Uniformity (STD%) Uniformity (STD%) 20 3.5 3.5 47.8 3.9 3.9 153.4 39.3 39.3

Dose
(MBq) Spill-over ratio (SOR) (STD %) water air 20 10.6 10.7 47.8 11.2 12.2 153.4 51.8 50.6

Specifically, in the case of the recovery coefficient, when radiopharmaceuticals with a radioactivity of 20 MBq and 47.8 MBq were injected, the ratio difference between the actual value and the measured value was close to 1 at 3 mm or more, whereas when radiopharmaceuticals with a radioactivity of 153.4 MBq were injected, the ratio difference between the actual value and the measured value was close to 1. In the case of injection, it was confirmed that the difference was 43-63% compared to the actual value at 1-4 mm and the value was 1 only at 5 mm. From the above results, rather than the case of injecting radiopharmaceuticals with a high radioactivity of 153.4MBq, low-activity radioactivity of 20MBq and 47.8MBq, which is within the range of the expected effective radioactivity derived in Example 3, was obtained. It can be seen that when the medicine is injected, the spatial resolution is even better.

In addition, in the case of uniformity, when radiopharmaceuticals of 20MBq and 47.8MBq of radioactivity were injected, the distribution of radioactivity in the region of interest had a standard deviation within 4%, whereas when radiopharmaceuticals of 153.4MBq of radioactivity were injected, It was confirmed that there was a deviation of 40%. From the above results, rather than the case of injecting a radiopharmaceutical with a high radioactivity of 153.4MBq, the low-activity radioactivity of 20MBq and 47.8MBq, which is within the range of the expected effective radioactivity derived in Example 3, was obtained. It can be seen that when pharmaceuticals are injected, the radioactive pharmaceuticals are distributed more evenly and a more homogeneous image can be obtained.

Lastly, the spillover ratio refers to the decrease in detection value due to scattering of radioactivity. When radiopharmaceuticals of 20MBq and 47.8MBq of radioactivity were injected, there was a deviation of less than 12% in water and air, whereas it was 153.4 It was confirmed that when MBq radioactive dose of radiopharmaceutical was injected, there was a deviation of more than 50%. From the above results, rather than the case of injecting radiopharmaceuticals with a high radioactivity of 153.4MBq, low-activity radioactivity of 20MBq and 47.8MBq, which is within the range of the expected effective radioactivity derived in Example 3, was obtained. It can be seen that when the medicine is injected, noise due to scattering is significantly reduced.

From this, it can be seen that 20 MBq to 47.8 MBq is the optimal radiation dose for obtaining excellent quality positron emission tomography images from the monkey brain.

Determine whether effective positron emission tomography images can be obtained at low-radiation doses within the optimal radiation dose range

In the case of positron emission tomography, as the amount of radiation used increases, the signal-to-noise ratio (SNR) increases, allowing better quality images to be obtained. Therefore, in this example, in order to confirm whether excellent quality positron emission tomography images can be obtained with radiopharmaceuticals with a radioactive amount of 47.8 MBq rather than 20 MBq, a monkey head fixation device having a structure as shown in FIG. 4 was designed. , using this, the monkey's head was fixed, and a radioactive dose of 47.8 MBq or 153.4 MBq of radiopharmaceuticals was injected into the posterior saphenous vein into a 117-month-old or 139-month-old monkey ( Cynomolgus Macaques ), and positron emission tomography was performed. And the amount and distribution of radiopharmaceuticals ingested into the brain were analyzed from the obtained positron emission tomography images.

As a result, as shown in Figures 5a and 5b, compared to the case of injecting a radiopharmaceutical with a high radioactivity (153.4MBq), the cerebellum was injected when a radiopharmaceutical with a low radioactivity (47.8MBq) was injected. Not only was it confirmed that a greater amount of radioactivity was absorbed (Figure 5a), but the SNR was also confirmed to be much better when a low-activity amount (47.8MBq) of radiopharmaceutical was injected (Figure 5b).

From the above results, even if high-radioactivity radiopharmaceuticals are not used, a low radioactivity within the range of the optimal radioactivity derived in Example 4 is sufficient, and rather, high-radioactivity radiopharmaceuticals are used. It can be seen that a better positron emission tomography image can be obtained than in the previous case.

Although preferred embodiments of the present invention have been described above by way of example, the scope of the present invention is not limited to the specific embodiments described above, and those skilled in the art will understand that the scope of the present invention is within the scope of the patent claims. Appropriate changes will be possible within it.

Claims (9)

Performing the process of injecting radioactive pharmaceuticals into a primate organ phantom and performing positron emission tomography (PET) multiple times while varying the amount of radioactivity;
Compare the radioactivity amount of the injected radiopharmaceutical with the radioactivity amount confirmed in the results of the positron emission tomography to select cases where the difference is within 25%, and in the selected cases, the minimum value of the radioactivity amount of the injected radiopharmaceutical and determining the maximum value;
varying the amount of radioactivity within the range of the minimum and maximum values, injecting radioactive pharmaceuticals into a quality control (QC) phantom, and performing positron emission tomography multiple times;
Confirming at least one image quality-related parameter from the results of positron emission tomography for the QC phantom; and
Selecting cases where the confirmed image quality-related parameters meet NEMA (National Electrical Manufacturers Association) standards, and confirming the minimum and maximum values of the radioactivity amount of the injected radiopharmaceutical in the selected cases;
Including,
Wherein the primate is non-human,
Method for determining optimal radiation dose for positron emission tomography in primates. delete In claim 1,
A method for determining the optimal radiation dose for positron emission tomography of a primate, wherein the primate is a monkey. In claim 1,
A method for determining the optimal radiation dose for positron emission tomography of a primate, wherein the organ is the brain. In claim 1,
The optimal radiation dose is a method of determining the optimal radiation dose for positron emission tomography of primates, wherein the optimal radiation dose is the minimum radiation dose of radiopharmaceuticals capable of obtaining a positron emission tomography image conforming to NEMA standards. In claim 1,
Comparing the radioactivity of the injected radiopharmaceutical and the radioactivity confirmed as a result of the positron emission tomography to select cases where the difference is within 25% is the difference between the actual radioactivity of the injected radiopharmaceutical and the radioactivity confirmed by the positron emission tomography. A method of determining the optimal radiation dose for primate positron emission tomography, which compares the radiation dose confirmed as a result of and selects cases where the difference is within 20%. In claim 1,
The image quality-related parameter is optimal for positron emission tomography of primates, wherein the image quality-related parameter is at least one selected from the group consisting of recovery coefficient, uniformity, and spill-over ratio. Method for determining radioactivity. In claim 7,
If the confirmed image quality-related parameters meet the NEMA standard, it is at least one selected from the group consisting of i) to iii) below. Method for determining the optimal radiation dose for positron emission tomography of primates:
i) when the recovery coefficient is in the range of 0.75 to 1.25;
ii) When the uniformity is 15.0% or less; and
iii) When the spillover rate in water or air is 15% or less. In claim 8,
If the confirmed image quality-related parameters meet the NEMA standard, all of i) to iii) above are satisfied. A method for determining the optimal radiation dose for positron emission tomography of primates.