JP2015189669A - Diagnostic reagent for positron emission tomography (pet) - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a PET imaging technique which can quantitatively evaluate neurogenesis in brain, and to provide a method for evaluating cranial nerve diseases or the effect of a therapeutic agent for cranial nerve diseases using the PET imaging technique.SOLUTION: We found out that a combination of [F] FLT or [C]-4DST which are PET tracer with a drug transporter inhibitor enables quantitative PET imaging of neurogenesis in brain. And we also found out that utilizing this PET imaging technique enables evaluation of cranial nerve diseases or evaluation of the effect of a therapeutic agent for cranial nerve diseases.

Description

  The present invention relates to a PET test agent comprising a combination of a PET tracer and a drug transporter inhibitor, as well as to the examination of neurogenesis in the brain of a living body, the test of cranial nerve disease, and the evaluation of the effect of a therapeutic agent for cranial nerve disease. It relates to the use of PET test drugs.

Neurogenesis in the adult brain occurs only in limited areas such as the lateral ventricle and the hippocampus. This phenomenon was observed in 2010 by a German research group using 3'-deoxy-3 '-[ ¹⁸ F] fluorothymidine ([ ¹⁸ F] FLT), a PET tracer for dividing cells. It was reported for the first time by performing PET imaging (Non-patent Document 1). In this report, [ ¹⁸ F] FLT was found to be very small but accumulated in each neurogenesis region (periventricular and hippocampus). However, SUV (Standard Uptake Value) indicating the intensity of [ ¹⁸ F] FLT accumulation in each region is around 0.1, and the value (0.08) in the region where neurogenesis has not occurred (there are few dividing cells) There was almost no difference. For this reason, it is very difficult to quantitatively evaluate a change (particularly a decrease) in neurogenesis by this method.

On the other hand, attempts have been made to increase the accumulation of PET tracers in the brain by using drug transporter inhibitors. For example, in rats, guinea pigs, monkeys, the amounts of PET tracers [ ¹¹ C] verapamil, [ ¹¹ C] GR205171, and [ ¹⁸ F] artanserin that reach the brain are P-glycoprotein (MDR1) inhibitors It is reported that it increases by administration of cyclosporine A or tarikidal (Non-patent Documents 2 and 3).

Rueger et al., J. Neurosci., 2010, 30 (18): 6454-60 Syvanen et al., Drug Metab. Dispos., 2009, 37 (3): 635-43 Bankstahl et al., J. Nucl. Med., 2008, 49 (8): 1328-35

  The present invention has been made in view of the above-described problems of the prior art, and an object thereof is to provide a PET imaging technique capable of quantitatively evaluating neurogenesis in the brain. A further object of the present invention is to provide a method for evaluating cranial nerve diseases and evaluating the effects of therapeutic agents for cranial nerve diseases using the PET imaging technique.

The present inventors have intensively studied to achieve the above object. Specifically, [ ¹⁸ F] FLT, 9-[(3- [ ¹⁸ F] fluoro-1-hydroxy-2-propoxy) methyl] guanine ([ ¹⁸ F] FHPG), 9- (4- [ ¹⁸ F] Fluoro-3-hydroxymethylbutyl) guanine ([ ¹⁸ F] FHBG), 4 ′-[methyl- ¹¹ C] thiothymidine ([ ¹¹ C] -4DST) is selected as a drug transporter inhibitor, A drug transporter inhibitor against the accumulation of PET tracers in the neurogenesis region (periventricular and hippocampus) of the brain, selecting probenecid, a multidrug resistance-related protein (MRP) inhibitor, and cyclosporin A, an MDR1 inhibitor The impact was evaluated.

As a result, the present inventors, the ^[18 F] FLT as PET tracers, in the case of using probenecid as a drug transporter inhibitor, in neurogenesis region (lateral periventricular and hippocampus) ^[18 F] It was found that the accumulated intensity (SUV value) of FLT increased about twice. Among these neurogenesis areas, higher accumulation intensity was observed around the lateral ventricle than in the hippocampus. This is because the neurogenesis around the lateral ventricle of rodents is in the hippocampus / dentate gyrus. Previous reports of higher than newborn (Jin et al., Aging Cell, 2003, 2 (3): 175-183, Isgor and Watson, Neuroscience 2005, 134 (3): 847-856, Abrous et al. , 2005, 85 (2): 523-569). Therefore, according to this PET imaging technique, it is possible to distinguish and evaluate not only the difference between the neurogenesis area and the non-neuron area but also the difference in the degree of neurogenesis in the neurogenesis area.

In addition, the present inventors evaluated the hippocampal neurogenesis in the depression model animal by this PET imaging technique, and the accumulation intensity of [ ¹⁸ F] FLT in the depression model animal was increased in the control group by administration of the antidepressant. It was found that the accumulated strength of [ ¹⁸ F] FLT recovered. Therefore, if this PET imaging method is used, it is possible to examine cranial nerve diseases and evaluate the effects of therapeutic agents for cranial nerve diseases.

Furthermore, when [ ¹¹ C] -4DST was used as a PET tracer, the present inventors, regardless of whether probenecid or cyclosporin A was used as a drug transporter inhibitor, We also found that the accumulation intensity of [ ¹¹ C] -4DST in (and hippocampus) increased.

Therefore, the present invention provides a PET imaging technique using any one of [ ¹⁸ F] FLT and [ ¹¹ C] -4DST and a drug transporter inhibitor, as well as evaluation of cranial nerve diseases using the PET imaging technique. More specifically, the following is provided for use in the evaluation of the effects of therapeutic agents for cranial nerve diseases.

[1] 3'-deoxy -3 '- ^[18 F] fluoro-thymidine and 4' - [methyl - ¹¹ C] PET test agent comprising a combination of any of the PET tracer and drug transporter inhibitor of thiothymidine.

[2] The PET test agent according to [1], wherein the PET tracer is 3′-deoxy-3 ′-[ ¹⁸ F] fluorothymidine and the drug transporter inhibitor is an MRP inhibitor.

  [3] The PET test agent according to [2], wherein the drug transporter inhibitor is probenecid.

[4] The PET test agent according to [3], wherein the PET tracer is 4 ′-[methyl- ¹¹ C] thiothymidine, and the drug transporter inhibitor is an MRP inhibitor or an MDR1 inhibitor.

  [5] The PET test agent according to [4], wherein the drug transporter inhibitor is probenecid or cyclosporin A.

  [6] A method for examining neurogenesis in the brain of a living body, comprising administering the PET test agent according to any one of [1] to [5] to a living body and performing PET imaging of the brain of the living body.

  [7] Collect PET imaging data for neurogenesis in the living brain, including PET imaging of the living brain to which the PET test agent according to any one of [1] to [5] is administered how to.

  [8] A method for examining cranial nerve diseases, comprising administering the PET test agent according to any one of [1] to [5] to a living body, and performing PET imaging of the brain of the living body.

  [9] A method for collecting PET imaging data for cranial nerve disease testing, comprising PET imaging of a living body brain administered with the PET test agent according to any one of [1] to [5].

  [10] A method for evaluating the effect of a therapeutic agent for cranial nerve disease, wherein the PET test agent according to any one of [1] to [5] is applied to a cranial nerve disease patient or a cranial nerve disease model animal treated with a cranial nerve disease therapeutic agent And PET imaging of the brain of the patient or animal.

  [11] A method for collecting PET imaging data for evaluating the effect of a therapeutic agent for cranial nerve disease, which is treated with the therapeutic agent for cranial nerve disease, and the PET examination according to any one of [1] to [5] A method comprising PET imaging of the brain of a cranial nerve disease patient or a cranial nerve disease model animal to which a drug is administered.

So far, it has been difficult to non-invasively and quantitatively image mammalian neurogenesis in vivo, but the present invention combined with drug transporter inhibitors can increase the amount of PET tracer that can reach the brain. A PET imaging method for neurogenesis with excellent quantification has been established. In particular, when [ ¹⁸ F] FLT is used as a PET tracer and probenecid is used as a drug transporter inhibitor, not only the difference between the neurogenesis and non-neurogenesis regions, but also the degree of neurogenesis in the neurogenesis region As a result, it was possible to distinguish and evaluate the results.

  In vivo imaging of neurogenesis in the brain (especially in the hippocampus) with the PET imaging technology of the present invention enables not only quantitative measurement of brain functions such as memory and learning, but also exercise and health foods. It is possible to objectively evaluate the good aging effect, and it is also possible to evaluate the effect of a cranial nerve disease test or a cranial nerve disease therapeutic agent.

It is a diagram showing the results of evaluating the effect of probenecid for ^[18 F] FLT accumulation in neurogenesis region (lateral periventricular and hippocampus, dentate gyrus). a is, PET images image has been detected ^[18 F] FLT integrated in the surrounding lateral ventricles, b is a graph showing the ^[18 F] FLT integrated intensity (SUV) in the surrounding lateral ventricle. c is, PET images image has been detected ^[18 F] FLT integrated in the hippocampus, dentate gyrus, d is a graph showing the ^[18 F] FLT integrated intensity (SUV) in the hippocampus, dentate gyrus. It is a graph showing the ^[18 F] FLT integrated intensity in the neurogenic regions (lateral periventricular and hippocampus, dentate gyrus) and the reference region (thalamus). Various drug transporter inhibitors (provenesid) for accumulation of various PET tracers ([ ¹⁸ F] FLT, [ ¹⁸ F] FHPG, or [ ¹⁸ F] FHBG) in the neurogenesis region (perilateral ventricle and hippocampal / dentate gyrus) Or it is an image which shows the result of having evaluated the influence of cyclosporin A). It is an image image which shows the result of having evaluated the influence of various drug transporter inhibitors (provenesid or cyclosporin A) on the accumulation of [ ¹¹ C] -4DST in the neurogenesis region (perilateral ventricle and hippocampus / dentate gyrus). The graph which shows the result of evaluating the effect of an antidepressant on a depressive model animal by the [ ¹⁸ F] FLT accumulation intensity in the neurogenesis area (periventricular and hippocampus / dentate gyrus) and reference area (thalamus) of the animal It is.

The present invention provides a PET test agent comprising a combination of a PET tracer of [ ¹⁸ F] FLT and [ ¹¹ C] -4DST and a drug transporter inhibitor.

  In the present invention, “PET tracer” means a molecular probe labeled with a positron nuclide.

  In addition, the “drug transporter” generally means a protein that transports and transports a drug, and in the present invention, in particular, it is expressed at the blood brain barrier (BBB), and the mechanism of drug drainage from the brain tissue Means the protein responsible for Examples of such drug transporters include, but are not limited to, MRP, MDR1, and breast cancer resistance protein (BCRP).

The PET test agent of the present invention comprises a combination of a PET tracer of either [ ¹⁸ F] FLT and [ ¹¹ C] -4DST and a drug transporter inhibitor. Here, the “combination” means that the PET tracer and the drug transporter inhibitor may be prepared as separate drugs or as a single drug. In addition, the PET tracer and the drug transporter inhibitor need not be administered simultaneously as long as PET imaging is possible.

The “drug transporter inhibitor” in the present invention is not particularly limited as long as it has the effect of increasing the accumulation of PET tracer in the neurogenesis region of the brain. When the PET tracer is 3′-deoxy-3 ′-[ ¹⁸ F] fluorothymidine, the drug transporter inhibitor is preferably an MRP inhibitor. Examples of the MRP inhibitor include probenecid, MK571, and sulfinpyrazone. Among them, probenecid is particularly preferable. On the other hand, when the PET tracer is 4 ′-[methyl- ¹¹ C] thiothymidine, the drug transporter inhibitor is preferably an MRP inhibitor or an MDR1 inhibitor. Examples of the MRP inhibitor include those described above, and examples of the MDR1 inhibitor include cyclosporin A, taricidal, elacridal, and valspodal. Among them, probenecid or cyclosporin A is particularly preferable.

  The PET test drug of the present invention can be used as a clinical test drug for humans, and can also be used as a reagent for testing in animal experiments. The PET test agent of the present invention may contain a pharmacologically acceptable carrier, if necessary, in addition to the active ingredient. Examples of such carriers include isotonic agents, buffers, pH adjusters, solubilizers, stabilizers, and preservatives.

  The method for administering the PET test agent of the present invention may be parenteral or oral as long as PET imaging is possible. As an administration method, intravenous injection is particularly preferable. In the case of intravenous injection, the PET test agent of the present invention is usually administered as an injection in which the above active ingredient is dissolved in a suitable solvent (eg, physiological saline, sterile purified water).

In the case of [ ¹⁸ F] FLT, the dose of PET tracer in intravenous injection is usually 100 to 300 MBq / kg, preferably around 200 MBq / kg (for example, 150 to 250 MBq / kg). In the case of [ ¹¹ C] -4DST, it is usually 300 to 500 MBq / kg, preferably around 400 MBq / kg (for example, 350 to 450 MBq / kg).

  In the case of probenecid and cyclosporin A, the dosage for intravenous injection of the drug transporter inhibitor is usually 1 mg / kg to 200 mg / kg. In addition, when these drug transporter inhibitors are orally administered, the dose is usually larger than that in the case of intravenous injection, preferably 200 to 500 mg / kg.

  The order of administration of the PET tracer and the drug transporter inhibitor is not particularly limited as long as PET imaging is possible, but it is preferable to administer the drug transporter inhibitor first.

  When the PET test agent of the present invention is administered to a living body, the PET tracer accumulates in the neurogenesis region of the brain. The positrons emitted from this PET tracer combine with the nearby negatively charged electrons and disappear, and at this time, a pair of gamma rays are emitted in the 180 degree direction. A pair of gamma rays simultaneously emitted in the opposite direction is detected by a PET apparatus. A tomographic image is obtained by detecting a large number of emitted gamma rays and processing the information with a computer. Such a PET imaging technique and the apparatus used are well known to those skilled in the art.

  According to the PET test agent of the present invention, it has been found that it is possible to quantitatively image neurogenesis in a living brain. Accordingly, the present invention provides a method for examining neurogenesis in a living brain, which comprises administering the PET test agent to a living body and performing PET imaging of the living brain. In the present invention, “living body” means living human and animal bodies. The animal is not particularly limited as long as PET imaging is possible in the brain, and may be an experimental animal, a pet animal, a domestic animal, or an animal for other purposes. Also good. Examples of animals include, but are not limited to, mice, rats, guinea pigs, rabbits, dogs, cats, cows, horses, sheep, monkeys, chimpanzees, and the like. In this method, the level of PET tracer accumulation indicated by PET imaging of the neurogenesis region of the brain is an indicator of the level of neurogenesis. It is known that neurogenesis in the adult brain occurs only in a limited area such as the lateral ventricle and the hippocampus. Therefore, in the inspection method of the present invention, the periventricular region of the brain and the hippocampus are particularly preferable as inspection targets. The present invention further provides a method for collecting PET imaging data for examination of neurogenesis in the living brain, which comprises PET imaging of the living brain to which the PET test agent is administered.

  According to the PET test agent of the present invention, it has been found that it is possible to quantitatively image a decrease in neurogenesis in the hippocampus of a cranial nerve disease animal. Therefore, the present invention provides a method for examining cranial nerve diseases, comprising administering the PET test agent to a living body and performing PET imaging of the brain of the living body. In this method, the low level of PET tracer accumulation shown by PET imaging of the neurogenesis region of the brain is an indicator of cranial nerve disease morbidity. As a control, for example, the level of PET tracer accumulation in healthy bodies (healthy humans and animals) can be used. The “cranial nerve disease” to be examined is not particularly limited as long as it is a disease related to a decrease in cerebral neurogenesis, and examples thereof include depression and Alzheimer's disease. The present invention further provides a method of collecting PET imaging data for cranial nerve disease examination, which comprises PET imaging of the brain of a living body to which the PET examination agent is administered.

  According to the PET test agent of the present invention, it has been found that it is possible to quantitatively image the recovery of a decrease in neurogenesis in the hippocampus of a cranial nerve disease animal by a therapeutic agent. Therefore, the present invention is a method for evaluating the effect of a therapeutic agent for cranial nerve disease, wherein the PET test agent is administered to a cranial nerve disease patient or a cranial nerve disease model animal treated with the cranial nerve disease therapeutic agent, and the patient or animal A method comprising PET imaging of the brain is provided. In the present invention, “patient” means a human suffering from a specific disease. In addition, the “model animal” means an animal produced so that symptoms similar to those of a human disease occur. The model animal is not particularly limited as long as the same symptoms as those of human diseases occur, and the above animals can be exemplified. Further, the “cranial nerve disease therapeutic agent” may be a compound that has already been found to have a therapeutic effect, or may be a compound for testing whether or not it has a therapeutic effect (that is, a therapeutic drug candidate). . As a result of PET imaging of the neurogenesis region, if there is a significant increase in PET tracer accumulation compared to cranial nerve disease patients or cranial nerve disease model animals not treated with cranial nerve disease treatment drugs, the cranial nerve disease treatment drug is Evaluated as effective. Conversely, if there is no significant increase in PET tracer accumulation compared to a cranial nerve disease patient or cranial nerve disease model animal that has not been treated with a cranial nerve disease treatment drug, the cranial nerve disease treatment drug is evaluated as ineffective. The When this method is applied to a plurality of therapeutic drug candidates, it is possible to screen for cranial nerve disease therapeutic drugs. The present invention further relates to a method of collecting PET imaging data for evaluating the effect of a therapeutic agent for cranial nerve disease, which is treated with a therapeutic agent for cranial nerve disease, and to which a cranial nerve disease patient to which the PET test agent is administered or A method comprising PET imaging of the brain of a cranial nerve disease model animal is also provided.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not limited to a following example.

[Example 1] PET imaging in the brain neurogenesis region using a PET tracer and a drug transporter inhibitor (1) Wistar male rats (8-12 weeks old) were used as experimental animals. PET imaging was performed using a PET camera for small animals (microPET Focus-220). A drug transporter inhibitor probenecid (10,100 mg / kg) or vehicle is administered intravenously to rats that have been treated with isoflurane anesthesia (4.0 at introduction, maintenance 1.5), and PET tracer [ ¹⁸ F] FLT 5 to 15 minutes after administration (20MBq / 100g BW) was administered intravenously and then scanned for 90 minutes. PET image data was reconstructed by FBP (filtered backprojection) method and analyzed using PMOD software. The reconstructed PET image is matched to the MR image of the rat brain. [ ¹⁸ F] FLT integrated intensity in the region of interest (perilateral ventricle, hippocampus / dentate gyrus, thalamus) and whole brain based on the MR image Was calculated as SUV (Standard Uptake Value). Regarding the region of interest, the periventricular and hippocampal / dentate gyrus were set as the neurogenesis region, and the thalamus was set as the reference (having almost no dividing cells) region. The image data used for SUV calculation was image data 45 to 90 minutes after administration of [ ¹⁸ F] FLT. Variations in [ ¹⁸ F] FLT brain reach among individuals were corrected using SUV in the whole brain.

FIG. 1 shows the effect of probenecid, a drug transporter inhibitor, on the increase of [ ¹⁸ F] FLT in the brain. Probenecid 100 mg / kg increased [ ¹⁸ F] FLT accumulation in the neurogenesis area (periventricular and hippocampal / dentate gyrus) (FIGS. 1a and 1c: PET images). When ROI analysis was performed in each neurogenesis region (perilateral ventricle and hippocampus / dentate gyrus), the SUV in each region of the solvent administration group was 0.12 (FIGS. 1b and 1d). The SUVs in the periventricular and hippocampal / dental gyrus in the probenecid 100 mg / kg administration group were 0.25 (FIG. 1b) and 0.22 (FIG. 1d), respectively. Furthermore, the SUVs in the probenecid 10 mg / kg group were 0.20 (Fig. 1b) and 0.18 (Fig. 1d), respectively, and [ ¹⁸ F] in both neurogenesis areas (periventricular and hippocampal / dentate gyrus) with probenecid A dose-dependent effect on the enhancement of FLT accumulation was observed (FIGS. 1b and 1d). In addition, as for the thalamus as the reference region, SUV increased slightly with administration of probenecid 100 mg / kg, but increased [ ¹⁸ F] FLT accumulation in the neurogenesis region (perilateral ventricle and hippocampus / dentate gyrus) Compared to the effect, it was low (Fig. 2). The difference in SUV between the neurogenesis region and the reference region makes it possible to quantitatively evaluate changes in neurogenesis.

  In addition, probenecid 100 mg / kg administration showed a clear difference in SUV (perilateral ventricle: 0.25 v.s. hippocampus / dentate gyrus: 0.22) in both neurogenesis areas (Fig. 2). This is considered to reflect the difference in the degree of neurogenesis in both neurogenesis regions. Immunostaining has revealed that neurogenesis around the lateral ventricle in rodents is 10-50 times higher than that in the hippocampus and dentate gyrus. This fact shows that this PET imaging technique is excellent in quantitativeness.

(2) Furthermore, ex vivo experiments were conducted on combinations of multiple PET tracers and multiple drug transporter inhibitors. Specifically, in addition to [ ¹⁸ F] FLT as a PET tracer, [ ¹⁸ F] FHPG, [ ¹⁸ F] FHBG, and [ ¹¹ C] -4DST are selected and are MRP inhibitors as drug transporter inhibitors In addition to probenecid, MDR1 inhibitor cyclosporin A was selected. The amount of PET tracer used in this experiment was 200 MBq / kg for [ ¹⁸ F] FLT, 200 MBq / kg for [ ¹⁸ F] FHPG, 200 MBq / kg for [ ¹⁸ F] FHBG, and [ ¹¹ C] -4DST for 400MBq / kg. In addition, the amount of drug transporter inhibitor probenecid or cyclosporin A used is 25 mg / kg (when [ ¹⁸ F] FLT, [ ¹⁸ F] FHBG or [ ¹¹ C] -4DST is used) or 50 mg / kg ([ ¹⁸ F] FHPG).

As a result of this experiment, with the combination of [ ¹⁸ F] FLT and probenecid, as in (1) above, high accumulation intensity of [ ¹⁸ F] FLT was observed in the neurogenesis region (perilateral ventricle and hippocampus / dentate gyrus). It was observed, but not with the combination of [ ¹⁸ F] FLT and cyclosporin A (Figure 3). In the case of using the ^[11 C] -4DST as PET tracers, even in the case of using any of probenecid and cyclosporin A as a drug transporter inhibitor, in neurogenesis region (lateral periventricular and hippocampus) ^[11 C] A high accumulation intensity of -4DST was observed (Fig. 4). None of the other combinations showed high PET tracer accumulation intensity in the neurogenesis region (periventricular and hippocampus). In the combination of [ ¹⁸ F] FHPG and cyclosporin A, nonspecific accumulation (accumulation outside the neurogenesis region) was observed.

[Example 2] Application to a cranial nerve disease model animal A depression model animal was prepared by daily administration of corticosterone (40 m / kg). Depression model animals were used to perform PET imaging and quantitatively monitor the degree of neurogenesis. In addition, an antidepressant (fluoxetine, a type of SSRI) was administered to a depression model animal, and the recovery effect of hippocampal neurogenesis that decreased due to depression was monitored by PET imaging.

As a result, [ ¹⁸ F] FLT accumulation in the depressive model rat hippocampus was clearly reduced compared to the control group (0.235 vs 0.272 control group) (FIG. 5). On the other hand, the degree of [ ¹⁸ F] FLT accumulation around the lateral ventricle and the thalamus is the same in the control group (side ventricle: 0.287, thalamus: 0.160) and depression model rat group (side ventricle: 0.287, thalamus: 0.166). Level (Figure 5). From these results, it was shown that the decrease in hippocampal neurogenesis observed in depression model animals can be quantitatively evaluated using the PET imaging method.

  It is well known that when fluoxetine, an antidepressant, is continuously administered to a depression model animal for 3-4 weeks, reduced hippocampal neurogenesis is recovered in the depression model animal. When this phenomenon was confirmed by PET imaging, the hippocampus SUV in the hippocampus of the depressive model rat was 0.235, whereas the hippocampal SUV in the group administered with the antidepressant (fluoxetine) was 0.262. It was confirmed that the level recovered to a level close to the group (SUV: 0.272) (Fig. 5). From the above results, it was shown that this PET imaging method is useful as a means for diagnosing cranial nerve diseases and determining the effects of therapeutic agents for cranial nerve diseases.

  As described above, according to the present invention, it is possible to quantitatively perform PET imaging of neurogenesis in the brain. This PET imaging technique can be used for examination of cranial nerve diseases and evaluation of the effects of therapeutic agents for cranial nerve diseases. Therefore, the present invention can greatly contribute particularly to clinical PET examinations.

Claims (8)

A PET test agent comprising a combination of a PET tracer and a drug transporter inhibitor of any of 3′-deoxy-3 ′-[ ¹⁸ F] fluorothymidine and 4 ′-[methyl- ¹¹ C] thiothymidine. The PET test agent according to claim 1, wherein the PET tracer is 3'-deoxy-3 '-[ ¹⁸ F] fluorothymidine, and the drug transporter inhibitor is an MRP inhibitor.   The PET test agent according to claim 2, wherein the drug transporter inhibitor is probenecid. PET tracers 4 '- [methyl - ¹¹ C] a thiothymidine, drug transporter inhibitor is an MRP inhibitor or MDR1 inhibitor, PET diagnostic agent of claim 3.   The PET test agent according to claim 4, wherein the drug transporter inhibitor is probenecid or cyclosporin A.   A method for collecting PET imaging data for neurogenesis in a living body brain, comprising PET imaging of the living body brain to which the PET test agent according to claim 1 is administered.   A method for collecting PET imaging data for cranial nerve disease testing, comprising PET imaging of the brain of a living body to which the PET test agent according to claim 1 is administered.   A method for collecting PET imaging data for evaluating the effect of a therapeutic agent for cranial nerve disease, wherein the PET imaging data is treated with the therapeutic agent for cranial nerve disease, and the PET test agent according to claim 1 is administered. A method comprising PET imaging of the brain of a neurological disease patient or a neurological disease model animal.