DRUG MASTER FILE: [18F]FDG



DRUG MASTER FILE: [11C]BMP

1. Name of Radiopharmaceutical (active ingredient)

N-[11C]Methylpiperidinyl butyrate ([11C]BMP)

2. Indicate the chemical structure for low molecular weight drug molecules

(not required for antibodies, proteins, or polymeric agents)

3. Has an Investigational New Drug (IND) application been filed for this radiopharmaceutical?

NO:

YES:

If Yes:

IND #      

Institution:      

4. State specific details of techniques to analyze and quantify the compound

(ex: spectrophotometer – make, settings, sample dilutions, etc.)

The radiochemical and chemical purity of each batch of the drug product will be determined utilizing high pressure liquid chromatography (HPLC), and compared to an authentic sample of N-methylpiperidinyl butyrate prepared using [12C]CH3I and which has been characterized by melting point, nmr spectroscopy and high resolution (exact mass) mass spectroscopy.

Analytical reverse phase HPLC will be done using a 4.6 mm x 250 mm reverse phase C-8, 5 µM particle column (PHENOMENEX Ultremex), with mixture of acetonitrile/50 mM ammonium formate, 25/75, at 1.0 ml/min. Twenty-five (25) microliters of sample consisting of a known volume (15 μL) of radiotracer solution and a known mass (25 μg) of [12CH3]BMP are injected onto the column. Detection of mass is done using a flow UV detector operating at 220 nm and radioactivity using a flow radioactivity detector (Beckman 170 Radioisotope Detector). The retention time for [11C]BMP is 8.5 - 10 minutes. As retention times can vary identity of the radioactive drug is verified by co-elution with the analytical standard of BMP. Data from the UV and radioactivity detectors are then collected using a Hitachi Model D2500 recorder/integrator, which provides integration of all peaks and a printout of purity calculations. The mass (in μg/ml) of the [11C]BMP will be calculated as the difference between the measured integration value and the integrated peak from a standard of known injected mass.

4a. Active Ingredient and Quantity (milligrams) to be administered.

N-[11C]Methylpiperidinyl butyrate is the active ingredient and less than 25 µg will be administered per injection.

4b. Indicate the minimum detectable mass of the drug by HPLC analysis.

< 5 μg (in a 1 ml sample)

5. Radioisotopes

Carbon-11

5b. Total activity of each isotope per administration (injection, IV, oral, etc.)

6. Method of assaying radioisotope activity prior to administration

(ex: Capintec ion chamber, gamma counter, or liquid scintillation counter; include details of make, setting, type of standard, etc.)

Calibrated dose calibrators; Capintec CRC-12. Cross standardization to [137Cs] is performed daily; assay of each unit-dose container (syringe) prior to administration.

7. Radionuclidic Purity

(in %)

>99%

8. Significant radionuclidic impurities and means of assay

Carbon-11 is obtained without any radionuclidic impurities, as determined by observing the decay rate of a batch of product

9. Radiochemical Purity

(in %)

>92% at the time of injection

10. Significant radiochemical impurities and means of assay

(ex: Chromatographic techniques and procedure for analyzing radiochromatogram).

The radiochemical and chemical purity of each batch of the drug product will be determined utilizing high pressure liquid chromatography (HPLC), and compared to an authentic sample of N-methylpiperidinyl butyrate prepared using [12C]CH3I and which has been characterized by melting point, nmr spectroscopy and high resolution (exact mass) mass spectroscopy.

11. Provide evidence that the tracer will be stable over period of storage prior to administration.

(Give details of storage conditions and on-going quality assurance procedures for sterility, apyrogenicity, and radiochemical purity.)

The 20-min half-life of carbon-11 requires that the radiopharmaceuticals be administered to the patient within 40 min (maximum) of synthesis. Repeated injections of the drug product onto the analytical HPLC have demonstrated that the product is stable at room temperature for this period of time. The radiopharmaceuticals will be stored at room temperature prior to patient administration.

12. What, if any, toxic or pharmacological effects may occur?

(Attach pharmacological dose calculations based on data available from published literature or from other valid human studies).

(NOTE: If study is being performed under 9C, evidence must be presented that there will be no pharmacological effect in human subjects. In addition, references for pharmacological dose data must be listed below)

N-[11C]Methylpiperidinyl butyrate is a substrate for butyrylcholinesterase. In animal studies, BMP is rapidly cleaved in both the blood and brain, forming two metabolites, butyric acid and N-methylpiperidinol.

BMP is a one-carbon homolog of the radiotracer currently in routine clinical use at our institution, N-[11C]methylpiperidinyl propionate, and is a two-carbon homolog of the radiotracer N-[11C]methylpiperidinyl acetate which is in clinical use in Japan (REF). We have previously tested PMP for toxicity in animals and in humans (approved protocol IRB-95-395 (approved 8/31/95) see RCS-102 for PMP) and found no pharmacologic or toxicologic actions of PMP at any dose tested. No adverse effects have been observed for human administrations of PMP.

12b. Attach pharmacological dose calculations based on data available from published literature or from other valid human studies.

You may add supporting documentation for this question in the Supporting Documents section of question 21-3.2.1.

13. Route(s) of Administration

Intravenous injection

14. Provide detailed information on how the pharmaceutical quality of the radioactive drug will be assured at the time of administration.

Include the following:

• pH

• Sterility

• Apyrogenicity

• Identify (chemical and radiochemical purity)

• Concentration

a. pH

A small amount of each batch of the final drug products will be spotted on Merck pH paper. The pH will be in the physiological range (4.5-8.0) and will be consistent from batch to batch.

b. Sterility/Apyrogenicity

During preclinical studies, the final drug product was produced utilizing established synthesis procedures [See appended Master Formula Card]. When tested as described below, the prepared batches were sterile and pyrogen-free. During clinical trials, the radioactive drug product will be produced utilizing these established procedures and a synthesis apparatus which will be appropriately maintained to assure that each batch of the drug product will be sterile and pyrogen-free. Sterility and bacterial endotoxin tests will be routinely performed on batches of the drug product in an ex post facto manner utilizing residual samples.

An aliquot of the final drug products will be inoculated into each of the appropriate sterility test media and incubated according to USP recommendations:

i. Fluid Thioglycollate Media (BBL, Division of Becton-Dickinson Co., Cockeysville, MD): 14 days at 30-35° C.

ii. Soybean Casein Broth (BBL, Division of Becton-Dickinson Co., Cockeysville, MD): 14 days at 20-25° C.

Positive growth is indicated by cloudiness in the culture media. Results will be compared to positive and negative controls. The efficacy of utilizing a 0.22 µm membrane filter for terminal sterilization [See appended Master Formula Card] warrants release of the drug products for patient administration prior to results of sterility testing as stipulated by current USP.

An aliquot of the final drug product will be tested for the presence of bacterial endotoxin utilizing the Limulus Amebocyte Lysate (LAL) Test with positive sample, positive, and negative controls. The currently used LAL test reagents are manufactured by Endosafe Inc., Charleston, SC under U.S. License No. 1073. Positive results are indicated by the presence of a firm gel that adheres to the bottom of the test tube when placed in the inverted position. Negative results are indicated if the contents slide down the side of the test tube when placed in the inverted position. Qualitative and quantitative test procedures will be utilized as appropriate to assure that the established USP endotoxin limit (175 EU per dose) for radiopharmaceuticals is not exceeded.

c. Identify (chemical and radiochemical purity)

The radiochemical and chemical purity of each batch of the drug product will be determined utilizing high pressure liquid chromatography (HPLC), and compared to an authentic sample of N-methylpiperidinyl butyrate prepared using [12C]CH3I and which has been characterized by melting point, nmr spectroscopy and high resolution (exact mass) mass spectroscopy.

Analytical reverse phase HPLC will be done using a 4.6 x 250 mm reverse phase C8 column (Ultremex), with 1:3 mixture of acetonitrile/50 mM ammonium formate, at 1.0 ml/min. Twenty-five (25) microliters of sample consisting of a known volume (15 μL) of radiotracer solution and a known mass (25 μg) of [12CH3]BMP are injected onto the column. Detection of mass is done using a flow UV detector operating at 220 nm and radioactivity using a flow radioactivity detector (Beckman 170 Radioisotope Detector). The retention time for [11C]BMP is 8.5 - 10 minutes. As retention times can vary identity of the radioactive drug is verified by co-elution with the analytical standard of BMP. Data from the UV and radioactivity detectors are then collected using a recorder/integrator, which provides integration of all peaks and a printout of purity calculations. The mass (in (g/ml) of the [11C]BMP will be calculated as the difference between the measured integration value and the integrated peak from a standard of known injected mass.

d. Concentration

i. Mass Concentration (mass/volume)

Range: 1.0 – 8.0 μg/ml

Mass concentration will be determined using HPLC, by comparison of UV absorbance intensity with a standard of known concentration.

ii. Activity Concentration (activity/volume)

A calibrated dose calibrator will be utilized for the determination of the total radioactivity contained in each batch of the drug products. The expected total radioactivity per batch will be in the range of 20 to 200 mCi. The expected volume will be 10 ml resulting in a concentration of 2 – 20 mCi/mL for each of the radiopharmaceuticals.

iii. Specific Activity (activity per mass of drug)

> 300 Ci/mmol (end of synthesis)

For questions or concerns, contact:

Scott E. Snyder, Ph.D.

Assistant Research Scientist

Division of Nuclear Medicine

(734) 763-0902

Fax: (734) 764-0288

Email: snyderse@umich.edu

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