Professional Drug Information > L-methyl-11Methionine

Methionine C 11 (Systemic)

VA CLASSIFICATION
Primary: DX201



Another commonly used name is L-[methyl- ¹¹C]methionine.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Diagnostic aid, radioactive (neoplastic disease)—

Indications

Note: Because methionine C 11 is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this product.

Accepted

[Brain imaging, positron emission tomographic¹]—Positron emission tomography (PET) using methionine C 11 (MET-PET) is used to locate and differentiate primary brain tumors ^{{03} {09} {16} {37}}, and as a means of monitoring the therapeutic effect of tumor irradiation ^{{05} {22}}. In studies of patients with cerebral glioma, MET-PET delineated the extent of the cerebral glioma more clearly than computed tomography (CT) or magnetic resonance imaging (MRI) ^{{10} {16}}. In this group of patients, the rate of uptake of methionine C 11 was significantly higher in the lesions of patients with high-grade glioma than in those with low-grade glioma ^{{10} {16}}. However, when taking each case individually, it was difficult to evaluate the grade of malignancy only from the degree of methionine C 11 accumulation in the lesions ^{{16} {26}}. Consequently, the value of MET-PET may be greater in assessing the extent rather than the grade of malignancy of cerebral gliomas ^{16}.
—Also, in patients who have undergone surgical excision of a tumor, but in whom neurological symptoms return, MET-PET may provide early detection in cases of tumor recurrence ^{{09} {17}}. In addition, in patients with cerebral tumors who have undergone radiation therapy, MET-PET in combination with PET using fludeoxyglucose F 18 may improve the accuracy of differentiation of recurrent brain tumor from radiation necrosis ^{{09} {36} {38}}.
—MET-PET may be useful in differentiating between neoplastic and non-neoplastic origins of an intracerebral hemorrhage ^{{18} {31}}. A MET-PET study showed that between 22 and 45 days after an intracerebral hemorrhage, non-neoplastic hematomas showed increased methionine C 11 uptake that agreed with contrast-enhanced CT or magnetic resonance (MR) images ^{31}. However, between 14 and 68 days after the ictus, neoplastic hematomas showed increased methionine C 11 uptake that extended beyond the contrast-enhanced areas on CT or MR images ^{31}.

Acceptance not established
MET-PET is used for the detection and staging of various carcinomas, such as breast, lung, endometrial, ovarian, urinary bladder, lymphoma, melanoma, and head and neck tumors. ^{{06} {07} {08} {11} {12} {13} {14} {15} {19} {20} {21} {25} {27} {28} {29} {32} {33}} In general, there is an increased uptake of methionine C 11 in highly proliferative malignant tumors. However, the sensitivity and specificity of MET-PET, as well as its necessity to be combined with morphological imaging procedures, is still in the process of being established ^{42}.

¹ Not included in Canadian product labeling.

Physical Properties

Nuclear Data ^{01}

Radionuclide (half-life)	Mode of decay	Principal photon emissions (keV)	Mean number of emissions/ disintegration
C 11 (20.41 min)	Positron decay	Gamma (annihilation) (511)	2

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Carbon C 11 ( ¹¹CO2) may be produced by the ¹⁴N(p,alpha) ¹¹C nuclear reaction on a target of nitrogen gas ^{{01} {34}}. From a series of chemical reactions, ¹¹CO ₂ is converted to methyliodide, ¹¹CH ₃I, and then reacted with homocysteine to produce methionine C 11 ^{{01} {34} {42}}.

Mechanism of action/Effect:

Neoplastic disease (diagnosis)—Methionine is a naturally occurring amino acid. The accumulation of methionine in tissue is related to amino acid utilization processes, such as transport, protein synthesis, and transmethylation ^{01}. Methionine is needed for protein synthesis and as a precursor of S-adenosylmethionine, which is the most important biologic methyl group donor in several biochemical reactions in vivo (e.g., methylation of DNA) ^{{07} {08} {15}}. In addition, S-adenosylmethionine is essential as a precursor in polyamine synthesis pathways, and contributes to the transsulfuration pathway ^{{07} {08} {15}}. However, recent studies have suggested that tissue accumulation of methionine is primarily related to amino acid active transport rather than to protein synthesis rate ^{26}. Since these reactions are accelerated in malignant cells, while biosynthesis of methionine is deficient or extremely reduced in malignant tissues, tumor cells have a high demand for externally added methionine ^{{07} {08} {11} {15} {24}}. The increased utilization of methionine can be measured by positron emission tomography (PET) with radiolabeled methionine C 11 used as the tracer.


In studies of patients with brain gliomas and lung cancer, the accumulation of methionine C 11 appeared to be related to the histological grade of cancer ^{{05} {06} {07} {23}} and also correlated to the growth rate of each cell type ^{06}. PET imaging of non–small cell lung carcinoma has demonstrated a strong association between the uptake rate of methionine C 11 and the cellular DNA content of tumor cells and the proliferative activity of the tumor (i.e., where the nuclear DNA is duplicating [S-phase] or the DNA content is already doubled [G2/M-phase]) ^{{08} {15} {26} {30}}. In addition, in breast tumor studies, an association has been found between methionine C 11 uptake and the fraction of cells in the S-phase and also with tumor size ^{{07} {11}}.

Distribution:

Methionine C 11 uptake in tumors is a complex process, related to several factors, such as amino acid transport and metabolism of both cancer and stromal cells, and tumor blood flow ^{{04} {08} {26}}. In addition, passive diffusion across the blood-brain barrier may account for methionine C 11 uptake from blood into brain tumor tissue ^{{05} {35}}. Uptake of methionine C 11 in tumor tissue is rapid ^{{04} {07} {35}}. In breast tumors, a plateau is achieved at 10 to 15 minutes after injection of methionine C 11 ^{07}. Also, methionine C 11 has high accumulation in normal pancreas, liver, salivary glands, bone marrow, bowel, endometrium, and pelvic bones ^{{07} {08} {27} {29} {39}}.

Protein binding:

High (90%) ^{01}.

Biotransformation:

When methionine C 11 is taken up in the cell, it will either undergo integration into protein or incorporation of its methyl group into DNA and other compounds ^{{01} {15} {26}}. Metabolites include serine and cysteine ^{01}.

Time to peak diagnostic effect

For most studies, the region of interest with the highest average radioactivity concentration at 35 to 40 minutes after injection of methionine C 11 has been used for the standardized uptake value analysis ^{{05} {11} {27}}. In studies of patients with either non–small cell lung carcinoma or cerebral gliomas, the radioactivity trapped in tumors during the first 10 minutes was found to remain almost constant for up to 1 hour (with decay correction) after injection of methionine C 11 ^{{15} {37}}. In a group of patients with primary and metastatic melanoma, the radioactivity concentration of methionine C 11 initially increased rapidly, then became constant from 25 to 40 minutes postinjection, followed by a slight decline ^{27}.


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies to assess transplacental transfer of methionine C 11 have not been done in humans. The possibility of pregnancy should be assessed in women of childbearing potential. Clinical situations exist where the benefits to the patient and fetus, based on information derived from radiopharmaceutical use, outweigh the risks from fetal exposure to radiation. In this situation, the physician should use discretion and reduce the administered activity to the lowest practical amount. ^{40}

Breast-feeding

It is not known whether methionine C 11 is distributed into breast milk. However, due to the short physical half-life of methionine C 11, any excretion of this agent during lactation is unlikely to result in significant radiation exposure to the breast-feeding infant ^{42}.

Pediatrics

Appropriate studies on the relationship of age to the effects of methionine C 11 have not been performed in children. Safety and efficacy have not been established.


Geriatrics


Appropriate studies on the relationship of age to the effects of methionine C 11 have not been performed in the geriatric population. However, clinical trials and studies that included older patients were conducted, and geriatrics-specific problems that would limit the usefulness of this agent in the elderly are not expected ^{{05} {13} {18} {27} {31} {32} {34}}.

Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With results of this test

Due to medical problems or conditions
Inflammatory lesions, local    (localization of methionine C 11 may occur at these sites ^{27})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

See also Diagnostic interference

Risk-benefit should be considered when the following medical problem exists
Sensitivity to the radiopharmaceutical preparation


Side/Adverse Effects
There are no known side/adverse effects associated with the use of methionine C 11.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Radiopharmaceuticals (Diagnostic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use
Action in the body: Uptake of radioactivity in tumors may be visualized by external imaging

Small amounts of radioactivity used in diagnosis; radiation received is low and considered safe

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to the radiopharmaceutical preparation

Pregnancy—Risk to fetus from radiation exposure as opposed to benefit derived from use should be considered

Preparation for this test
Fasting for 3 to 5 hours before test may be required

Special preparatory instructions may apply; patient should inquire in advance

Precautions after having this test
No special precautions


General Dosing Information
Radiopharmaceuticals are to be administered only by or under the supervision of physicians who have had extensive training in the safe use and handling of radioactive materials and who are authorized by the appropriate Federal or State regulatory agency, if required, or, outside the U.S., the appropriate authority ^{{41} {42}}.

Fasting or a light protein-poor breakfast 3 to 5 hours before positron emission tomography (PET) imaging is sometimes recommended ^{{07} {11} {14} {19} {21} {27} {32} {34}}. Although tumor imaging with PET using methionine C 11 (MET-PET) can be performed even if the patient has not fasted, a standardized meal (e.g., liquid meal) may slightly decrease tumor uptake of methionine C 11 ^{21}.

Safety considerations for handling this radiopharmaceutical
Guidelines for the receipt, storage, handling, dispensing, and disposal of radioactive materials are available from scientific, professional, state, federal, and international bodies. Handling of this radiopharmaceutical should be limited to those individuals who are appropriately qualified and authorized. ^{02}


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

METHIONINE C 11 INJECTION USP

Note: Because methionine C 11 is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this product.


Usual adult administered activity
[Diagnosis of brain carcinoma]¹
Intravenous, 560 to 930 megabecquerels (15 to 25 millicuries) administered as a single injection usually into a peripheral vein of the upper extremity ^{{05} {42}}.

Note: In the detection and staging of various other carcinomas, the administered activity has ranged between 185 and 555 megabecquerels (5 to 15 millicuries) ^{42}.



Usual pediatric administered activity
Safety and efficacy have not been established in patients younger than 18 years of age.

Usual geriatric administered activity
See Usual adult administered activity .

Strength(s) usually available
U.S.—
Prepared on-site at various clinical facilities.

Canada—
Prepared on-site at various clinical facilities.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) ^{01}. Protect from freezing and shaking ^{01}.

Stability:
Preparations of methionine C 11 containing up to 4 gigabecquerels (108 millicuries) per 5 mL have been shown to be stable in aqueous solutions at pH levels between 5 and 7.5 for two hours at room temperature ^{01}.

Note: Caution—Radioactive material.

Developed: 08/24/1998

References

1. Stöcklin G, Pike VW, editors. Radiopharmaceuticals for positron emission tomography: methodological aspects. Boston: Kluwer Academic Publishers; 1993. p. 2, 5, 108-10.
   

2. Radiopharmaceuticals Advisory Panel Meeting, 4/96.
   

3. Mosskin M, von Holst H, Bergström M, et al. Positron emission tomography with ¹¹C-methionine and computed tomography of intracranial tumours compared with histopathologic examination of multiple biopsies. Acta Radiol 17; 28(6): 673-81.
   

4. Abe Y, Matsuzawa T, Itoh M, et al. Regional coupling of blood flow and methionine uptake in an experimental tumour assessed with autoradiography. Eur J Nucl Med 1988; 14: 388-92.
   

5. Derlon JM, Bourdet C, Bustany P, et al. [ ¹¹C] L-methionine uptake in gliomas. Neurosurgery 1989; 25: 720-8.
   

6. Fujiwara T, Matsuzawa T, Kubota K, et al. Relationship between histologic type of primary lung cancer and carbon-11-L-methionine uptake with positron emission tomography. J Nucl Med 1989; 30(1): 33-7.
   

7. Leskinen-Kallio S, Någren K, Lehikoinen P, et al. Uptake of C-11-methionine in breast cancer studied by PET: an association with the size of S-phase fraction. Br J Cancer 1991; 64: 1121-4.
   

8. Leskinen-Kallio S, Routsalainen U, Någren K, et al. Uptake of C-11-methionine and fluorodeoxyglucose in non-Hodgkin's lymphoma: a PET study. J Nucl Med 1991; 32(6): 1211-8.
   

9. Ogawa T, Kanno I, Shishido F, et al. Clinical value of PET with ¹⁸F-fluorodeoxyglucose and L-methyl- ¹¹C-methionine for diagnosis of recurrent brain tumor and radiation injury. Acta Radiol 1991 May; 32(3): 197-202.
   

10. Mineura K, Sasajima T, Kowada M, et al. Innovative approach in the diagnosis of gliomatosis cerebri using carbon-11-L-methionine positron emission tomography. J Nucl Med 1991 Apr; 32(4): 726-8.
    

11. Leskinen-Kallio S, Någren K, Lehikoinen P, et al. Carbon-11-methionine and PET is an effective method to image head and neck cancer. J Nucl Med 1992; 33(5): 691-5.
    

12. Huovinen R, Leskinen-Kallio S, Någren K, et al. Carbon-11-methionine and PET in evaluation of treatment response of breast cancer. Br J Cancer 1993; 67(4): 787-91.
    

13. Kubota K, Yamada S, Ishiwata K, et al. Evaluation of the treatment response of lung cancer with positron emission tomography and L-[methyl- ¹¹C]methionine: a preliminary study. Eur J Nucl Med 1993; 20(6): 495-501.
    

14. Lindholm P, Leskinen-Kallio S, Minn H, et al. Comparison of fluorine-18-fluorodeoxyglucose and carbon-11-methionine in head and neck cancer. J Nucl Med 1993; 34(10): 1711-6.
    

15. Miyazawa H, Arai T, Iio Masaaki, et al. PET imaging of non–small cell lung carcinoma with carbon-11-methionine: relationship between radioactivity uptake and flow-cytometric parameters. J Nucl Med 1993; 34(11): 1886-91.
    

16. Ogawa T, Shishido F, Kanno I, et al. Cerebral glioma: evaluation with methionine PET. Radiology 1993; 186(1): 45-53.
    

17. Viader F, Derlon JM, Petit-Taboue MC, et al. Recurrent oligodendroglioma diagnosed with ¹¹C-L-methionine and PET: a case report. Eur Neurol 1993; 33(3): 248-51.
    

18. Dethy S, Goldman S, Blecic S, et al. Carbon-11-methionine and fluorine-18-FDG PET study in brain hematoma. J Nucl Med 1994; 35(7): 1162-6.
    

19. Lapela M, Leskinen-Kallio S, Varpula M, et al. Imaging of uterine carcinoma by carbon-11-methionine and PET. J Nucl Med 1994; 35(10): 1618-23.
    

20. Letocha H, Ahlstrom H, Malmstrom PU, et al. Positron emission tomography with L-methyl- ¹¹C-methionine in the monitoring of therapy response in muscle-invasive transitional cell carcinoma of the urinary bladder. Br J Urol 1994; 74(6): 767-74.
    

21. Lindholm P, Leskinen-Kallio S, Kirvela O, et al. Head and neck cancer: effect of food ingestion on uptake of C-11-methionine. Radiology 1994; 190(3): 863-7.
    

22. Ogawa T, Kanno I, Hatazawa J, et al. Methionine PET for follow-up radiation therapy of primary lymphoma of the brain. Radiographics 1994; 14(1): 101-10.
    

23. Roelcke U. PET: brain tumor biochemistry. J Neurooncol 1994; 22(3): 275-9.
    

24. Hoshiya Y, Guo H, Kubota T, et al. Human tumors are methionine dependent in vivo. Anticancer Res 1995; 15(3): 717-8.
    

25. Jansson T, Westlin JE, Ahlstrom H, et al. Positron emission tomography studies in patients with locally advanced and/or metastatic breast cancer: a method for early therapy evaluation? J Clin Oncol 1995; 13(6): 1470-7.
    

26. Kubota R, Kubota K, Yamada S, et al. Methionine uptake by tumor tissue: a microautoradiographic comparison with FDG. J Nucl Med 1995; 36(3): 484-92.
    

27. Lindholm P, Leskinen S, Någren K, et al. Carbon-11-methionine PET imaging of malignant melanoma. J Nucl Med 1995; 36(10): 1806-10.
    

28. Lindholm P, Leskinen-Kallio S, Grenman R, et al. Evaluation of response to radiotherapy in head and neck cancer by positron emission tomography and [ ¹¹C]methionine. Int J Radiat Oncol Biol Phys 1995; 32(3): 787-94.
    

29. Lapela M, Leskinen-Kallio S, Varpula M, et al. Metabolic imaging of ovarian tumors with carbon-11-methionine: a PET study. J Nucl Med 1995; 36(12): 2196-200.
    

30. Minn H, Clavo AC, Grénman R, et al. In vitro comparison of cell proliferation kinetics and uptake of tritiated fluorodeoxyglucose and L-methionine in squamous-cell carcinoma of the head and neck. J Nucl Med 1995; 36(2): 252-8.
    

31. Ogawa T, Hatazawa J, Inugami A, et al. Carbon-11-methionine PET evaluation of intracerebral hematoma: distinguishing neoplastic from non-neoplastic hematoma. J Nucl Med 1995; 36(12): 2175-9.
    

32. Rodriguez M, Rehn S, Ahlstrom H, et al. Predicting malignancy grade with PET in non-Hodgkin's lymphoma. J Nucl Med 1995; 36(10): 1790-6.
    

33. Ahlstrom H, Malmstrom PU, Letocha H, et al. Positron emission tomography in the diagnosis and staging of urinary bladder cancer. Acta Radiol 1996; 37(2): 180-5.
    

34. Inoue T, Kim EE, Wong FCL, et al. Comparison of fluorine-18-fluorodeoxyglucose and carbon-11-methionine PET in detection of malignant tumors. J Nucl Med 1996; 37(9): 1472-6.
    

35. Roelcke U, Radu E, Ametamey S, et al. Association of rubidium and C-methionine uptake in brain tumors measured by positron emission tomography. J Neurooncol 1996; 27(2): 163-71.
    

36. Sasaki M, Ichiya Y, Kuwabara Y, et al. Hyperperfusion and hypermetabolism in brain radiation necrosis with epileptic activity. J Nucl Med 1996 Jul; 37(7): 1174-6.
    

37. Langen KJ, Ziemons K, Kiwit JC, et al. 3-[123]iodo-alpha-methyltyrosine and [methyl- ¹¹C]-L-methionine uptake in cerebral gliomas: a comparative study using SPECT and PET. J Nucl Med 1997 Apr; 38(4): 517-22.
    

38. Goldman S, Levivier M, Pirotte B, et al. Regional methionine and glucose uptake in high-grade gliomas: a comparative study on PET-guided stereotactic biopsy. J Nucl Med 1997 Sep; 38(9): 1459-62.
    

39. Leskinen S, Pulkki K, Knuuti J, et al. Transport of carbon-11-methionine is enhanced by insulin. J Nucl Med 1997 Dec; 38(12): 1967-9.
    

40. Radiopharmaceuticals Advisory Panel Meeting, 5/8/91.
    

41. Radiopharmaceuticals Advisory Panel Meeting, 8/4/92.
    

42. Reviewers' comments as of monograph revision of 3/98.
    

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