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Title: RADIOCHEMICAL PURITY TESTING

Version No: 3

Author: Beverley Ellis and Jim Ballinger

Date of Issue: May 2021

Review Date: May 2024

Version 1 issued 19 December 2012 Version History: Version 2 reviewed and updated 04 Jan 2015 Version 3 reviewed and updated May 2021

UKRG Information Resources, page 2

U.K. adiopharmacyG roup R

Radiochemical Purity Testing of

Contents

1.1 General description of thin-layer chromatographic (TLC) techniques

1.2 Consumables

1.3 Thin-layer chromatography of technetium radiopharmaceuticals – Full list

1.4 Thin-layer chromatography of technetium radiopharmaceuticals – Simplified strategy

1.5 Thin-layer chromatography of other radiopharmaceuticals

1.6 Solid-phase extraction cartridge methods 1.6.1 Consumables 1.6.2 General procedure 1.6.3 Preparation of reagents 1.6.4 Table of systems

1.7 [99mTc]exametazime extraction methods

1.8 High-pressure liquid chromatography (HPLC) 1.8.1 General procedure 1.8.2 HPLC systems for SPECT radiopharmaceuticals 1.8.3 HPLC systems for PET radiopharmaceuticals

1.9 Tips for performing radiochemical purity tests 1.9.1 Thin-layer chromatography 1.9.2 Cartridge/membrane filtration

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1.1 General description of thin-layer chromatographic (TLC) techniques

Radiochemical purity (RCP) is the proportion of the radioactivity which is present in the desired chemical form. It is sometimes called labelling efficiency. A minimum acceptable RCP is specified for each , in order that the impurities do not interfere with the quality of the image or result in an unacceptably high radiation dose to the patient (e.g. free iodide going to the thyroid gland).

99mTc labelled agents constitute the vast majority of the radiopharmaceuticals used in nuclear medicine. The main impurities which can be present are free 99m pertechnetate ( TcO4) and reduced hydrolysed (RH) Tc-99m colloid. Generally, two TLC systems are used, one to quantify each of the main impurities, and the % bound (RCP) is calculated by subtracting the total impurities from 100%.

Radiopharmaceutical TLC is generally performed using paper or fibreglass sheets (stationary phase) which are easily cut using scissors into narrow strips, from 1 x 6 cm to 2 x 20 cm. A spotting line is carefully marked in pencil 1-2 cm from the bottom of the strip. A solvent front may be marked near the other end of the strip. A drop of the radiopharmaceutical is placed on the spotting line and the strip is placed in a tank or tube containing the mobile phase (solvent) specified. When the strip is placed in the tank, the spot must remain above the level of the solvent. The solvent is allowed to migrate up the strip until it reaches the top or the pre-marked solvent front, then the strip is removed and allowed to dry.

There are two approaches to determining the distribution of radioactivity along the strip. One is to image the strip, using a radiochromatogram scanner, phosphor imager (digital autoradiography), or gamma camera. Quantification is then performed by placing regions of interest along the radiochromatogram. If imaging equipment is not available, the alternative is to cup the strip into two or more pieces and determine the activity in each portion using a dose calibrator or gamma counter, depending on the level of activity present. The “cut-and-count” technique has the disadvantage that the cut point(s) is/are based on the assumed chromatographic behaviour of the components which may be present. Although a reasonable profile could be obtained by cutting the strip into 10 or 20 portions, this is not practical for routine use.

For a more complete description of the theory and practice of RCP testing, the reader is referred to “Quality control methods for radiopharmaceuticals” by T Theobald and P Maltby in Sampson’s Textbook of Radiopharmacy (4th edition, T Theobald, editor, The Pharmaceutical Press, 2010).

Please note: The RCP method described in the Summary of Product Characteristics (SmPc) for a radiopharmaceutical is the authorised method. However, there are alternative methods that have been used in practice. Any alternative method must be appropriately validated before being implemented

UKRG Information Resources, page 4 into practice and should meet the requirements of the Ph Eur method 2.2.66/BP Appendix V on Detection and measurement of radioactivity and chromatography.

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1.2 Consumables

Stationary phases ITLC-SG Instant thin-layer chromatography, silica gel SGI0001, Agilent www.agilent.com ITLC-SA Instant thin-layer chromatography, silicic acid A120B12, Agilent 3MM Whatman 3MM chromatography paper No 1 Whatman No 1 chromatography paper Silica gel Silica gel 60, e.g. Merck Alumina Aluminium oxide, Bakerflex Cellulose Cellulose, e.g. Merck

Mobile phases Butanone 2-butanone = methyl ethyl ketone = MEK 1 M Sodium 82 mg/mL anhydrous sodium acetate or 136 mg/mL sodium acetate trihydrate 0.1 M Citrate 21 mg/mL monosodium citrate dihydrate 1 M Ammonium acetate 77 mg/mL ammonium acetate Mixtures of volatile solvents should be made freshly

1.3 Thin-layer chromatography of technetium radiopharmaceuticals - Full list

Rf Radiopharm- Stationary Rf Rf Tc- Mobile phase RH- Ref aceutical phase TcO4 bound Tc

Polar [99mTc]Pertechnetate ITLC-SG Acetone or saline 0.0 1.0 - [1] [99mTc] Tc- ITLC-SG or Acetone or 0.0 1.0 0.0 [2] MDP/HDP/DPD 3MM butanone ITLC-SG Saline (MDP) or 0.0 1.0 1.0 [2], 1 M Sodium M acetate (HDP/DPD) [99mTc]Tc-DTPA ITLC-SG or Acetone 0.0 1.0 0.0 [2] 3MM ITLC-SG or Saline 0.0 1.0 1.0 [2] 3MM [99mTc]Tc-DMSA 3MM Acetone 0.0 1.0 0.0 [2] ITLC-SA Butanol acidified 0.0 0.9 0.5 [3] with 0.3 M HCl [99mTc]Tc- ITLC-SG or Acetone 0.0 1.0 0.0 [2] Pyrophosphate 3MM ITLC-SG Water 0.0 1.0 1.0 [2] [99mTc]Tc-IDAs ITLC-SA 20% Sodium 0.0 1.0 0.0 [4] chloride 3MM (Spot Butanone 0.0 0.9 0.0 M must be dry) ITLC-SG Water or 50% 0.0 1.0 1.0 [4] acetonitrile

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[99mTc]Tc(V)-DMSA Silica gel Butanol-acetic 0.0 0.8 0.5 [5] acid-water (3:2:3)

Particulate [99mTc]Tc-MAA ITLC-SG or Acetone or saline 0.0 1.0 0.0 [2] 3MM [99mTc]Tc-Colloid (tin ITLC-SG or Acetone or saline 0.0 1.0 0.0 [2] colloid, nanocolloid) 3MM

Non-polar [99mTc]Sestamibi Alumina Ethanol 0.0 0.0 1.0 M (Pre-spot with ethanol; do not allow spot to dry) [99mTc]Tetrofosmin ITLC-SG Acetone- 0.0 1.0 0.5 [6] (Spot must be dichloromethane dry) (35:65) [99mTc]Tc-MAG3 ITLC-SG Ethyl acetate- 0.0 1.0 0.0 [7] butanone (3:2) No 1 - 0.0 1.0 0.0 [8] acetone-THF (1:1:2) ITLC-SG 50% Acetonitrile 0.0 1.0 1.0 [7] [99mTc]Exametazime ITLC-SG Butanone 0.0 1.0 1.0 [9] (HMPAO) ITLC-SG Saline 0.0 1.0 0.0 [9] No 1 50% Acetonitrile 0.0 1.0 1.0 [9]

Protein [99mTc]Tc-HSA ITLC-SG or Acetone 0.0 1.0 0.0 [10] 3MM ITLC-SG Ethanol- 0.0 1.0 1.0 [10] (Strip is pre- ammonia-water saturated with (2:1:5) human serum albumin and dried) [99mTc]Sulesomab ITLC-SG or Acetone, saline, 0.0 1.0 0.0 M (Leukoscan) 3MM or 0.1 M citrate [99mTc]Besilesomab ITLC-SG Butanone 0.0 1.0 0.0 M (Scintimun)

M = Monograph (pharmacopoeia or manufacturer)

Substitutions:

• In most cases, 2-butanone (methyl ethyl ketone, MEK) can be substituted for acetone • In most cases, water can be substituted for saline • In most cases, Whatman No 1 can be substituted for Whatman 3MM paper • In most cases, ITLC-SA can be substituted for ITLC-SG (not for MDP) • ACD can be substituted for 0.1 M citrate

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1.4 Thin-layer chromatography of technetium radiopharmaceuticals: Simplified strategy

System A-1 Impurity Free pertechnetate Radiopharmaceuticals MDP/HDP/DPD, DTPA, MAA, DMSA, DMSA(V), Nanocolloid, Tin colloid, Sulesomab, Besilesomab, HSA, Pertechnetate Stationary phase ITLC-SG Mobile phase 2-Butanone (MEK) Interpretation Origin – bound Front – free pertechnetate

System A-2 Impurity Reduced hydrolysed technetium Radiopharmaceuticals MDP/HDP/DPD, DTPA Stationary phase ITLC-SG Mobile phase Saline (MDP, DTPA) or 1 M sodium acetate (HDP/DPD) Interpretation Origin – reduced hydrolysed Front – bound

System B Radiopharmaceuticals Sestamibi Stationary phase Aluminium oxide (Bakerflex) Mobile phase Ethanol (95% or greater) Precautions Prespot with ethanol. Spot sample while still wet. Then allow to dry before developing Interpretation Origin – impurities Front – bound

System C Radiopharmaceuticals Tetrofosmin Stationary phase ITLC-SG Mobile phase Acetone-dichloromethane (35:65) Precautions Spot must be allowed to dry before developing Interpretation Origin – reduced hydrolysed Middle - bound Front – free pertechnetate

System D-1 Impurity Free pertechnetate Radiopharmaceutical MAG3 Stationary phase Whatman No 1 paper Mobile phase Chloroform-acetone-THF (1:1:2) Interpretation Origin – bound Front – free pertechnetate

System D-2 Impurity Reduced hydrolysed technetium Radiopharmaceutical MAG3, Mebrofenin Stationary phase ITLC-SG Mobile phase 50% Acetonitrile Interpretation Origin – reduced hydrolysed Front – bound

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System E Impurity Free pertechnetate Radiopharmaceutical Mebrofenin (HIDA) Stationary phase ITLC-SA Mobile phase 20% Sodium chloride Interpretation Origin – bound Front – free pertechnetate

System F-1 Impurity Free pertechnetate Radiopharmaceutical HMPAO Stationary phase ITLC-SG Mobile phase Saline Interpretation Origin – bound Front – free pertechnetate

System F-2 Impurities Reduced hydrolysed technetium + secondary complex Radiopharmaceutical HMPAO Stationary phase ITLC-SG Mobile phase 2-Butanone (MEK) Interpretation Origin – reduced hydrolysed and secondary complex Front – bound and free pertechnetate

System F-3 Impurity Reduced hydrolysed Radiopharmaceutical HMPAO Stationary phase Whatman No 1 paper Mobile phase 50% Acetonitrile Interpretation Origin – colloid Front – bound, free pertechnetate and secondary complex

System G Radiopharmaceutical Tc(V)-DMSA (pentavalent) Stationary phase Silica gel (not ITLC) Mobile phase Butanol-acetic acid-water (3:2:3) Interpretation Origin – reduced hydrolysed; Tc(III)-DMSA Middle – Tc(V)-DMSA Front – free pertechnetate

System H-1 Impurity Free 111In, 90Y, 177Lu, 68Ga Radiopharmaceutical Octreotide, DOTATATE Stationary phase ITLC-SG Mobile phase 0.1 M citrate Interpretation Origin – bound Front - free

System H-2 Impurity Colloidal 111In, 90Y, 177Lu, 68Ga Radiopharmaceutical Octreotide, DOTATATE Stationary phase ITLC-SG Mobile phase 1 M ammonium acetate-methanol (1:1) Interpretation Origin – colloid Front - bound

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System J Impurity Free fluoride Radiopharmaceutical FDG Stationary phase Silica gel Mobile phase Acetonitrile-water (95:5) Interpretation Origin – free fluoride Middle - bound

1.5 Thin-layer chromatography of other radiopharmaceuticals

Radiopharm- Stationary Rf Rf Mobile phase Ref aceutical phase free bound [123/131I]I-MIBG Silica gel Ethyl acetate-ethanol 0.6 0.0 [11] (1:1) [111In]In-DTPA ITLC-SG 10% Ammonium 0.1 1.0 [12] acetate- methanol (1:1) [111In]In-Octreotide ITLC-SG 0.1 M Citrate buffer 1.0 0.0 [13] [90Y/177Lu/68Ga] pH 5 Y/Lu/Ga- DOTA-TATE ITLC-SG 1 M Ammonium 0.0 1.0 [13] acetate-methanol (colloid) (1:1) 2-[18F]FDG Silica gel Acetonitrile-water 0.0 0.6 [14] (95:5) [18F]Fluoroethylcholine Silica gel Acetonitrile-saline 0.0 0.6 [15] (1:1) [123I] ITLC-SA Saline 1.0 0.0 [16] (Datscan) [123I] Silica gel Ethyl acetate- 0.0 0.7 [17] ammonium hydroxide (200:1) Silica gel Chloroform-acetic 0.0 0.3 [17] acid- water (65:35:5) [131I] Silica gel Chloroform-ethanol 0.0 0.7 [18] (1:1)

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1.6 Solid-phase extraction cartridge methods

1.6.1 Consumables

Solid phase extraction cartridges are available from various suppliers. The original brand was Sep-Pak by Waters Associates. Cartridges can be re-used several times after decay of radioactivity.

1.6.2 General procedure:

1. Pre-wet (“activate”) cartridge with 2-5 mL ethanol or methanol.

2. Prepare cartridge with 2-10 mL of preparation solvent.

3. Place a drop of the radiopharmaceutical in the inlet of the cartridge.

4. Elute sequentially with 2-10 mL quantities of eluates A, B, C and collect each in a separate tube; after the last eluate, force air through the cartridge to dry it.

5. Place the cartridge in another tube for measurement of residual activity.

6. Measure the activity in each tube in an ionisation chamber.

7. Calculate radiochemical purity as per table.

1.6.3 Preparation of reagents

Reagent Preparation 1 mM HCl 1 mL conc HCl per litre of distilled water (0.001 M HCl) PB for MAG3 0.01 M (10 mM) sodium phosphate buffer pH 6 Prepare 100 mL 0.01 M monosodium phosphate solution (NaH2PO4). Prepare 20 mL 0.01 M disodium phosphate solution (Na2HPO4). Add 10 mL disodium phosphate solution to 100 mL monosodium phosphate solution. pH should still be below 6. Add disodium phosphate solution dropwise until pH of 6 is obtained. PB for MIBG 0.1 M (100 mM) monosodium phosphate (NaH2PO4) THF tetrahydrofuran 10 mM NaOH (0.01 0.4 g dissolved in 1 litre of distilled water M NaOH) or dilute 1 mL 1 M NaOH with 99 mL distilled water

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1.6.4 Table of systems

Prepar- Radiophar- Type of ation A B C D Purity Ref maceutical cartridge solvent [99mTc]sestamibi Alumina N 0.5 mL 10 mL cartridge A/total [19] ethanol ethanol residue C-18 2 mL 2 mL 5 mL cartridge B/total [20] saline saline ethanol residue [99mTc]tetrofosmin C-18 2 mL 2 mL 5 mL cartridge B/total [21] saline saline ethanol residue Silica 5 mL 10 mL cartridge B/total [22] saline methanol- residue then 1 water mL air (70:30) over 2 minutes Silica 5 mL 10 mL 10 mL cartridge B/total [22] saline methanol- methanol- residue then 1 water saline mL air (70:30) (80:20) over 2 minutes [99mTc]Tc-MAG3 C-18 10 mL 10 mL 10 mL cartridge B/total M 1 mM 1 mM 50% residue HCl HCl ethanol C-18 10 mL 5 mL 5 mL 10 mL cartridge C/total M 1 mM 1 mM 0.5% 7% residue HCl HCl ethanol in ethanol PB in PB [99mTc]exametazime C-18 5 mL 5 mL cartridge B/total [23] saline saline residue [99mTc]Tc-IDAs C-18 10 mL 10 mL 10 mL cartridge B/total [24] 1 mM 1 mM 95% residue HCl HCl ethanol [111In]In-octreotide C-18 10 mL 5 mL 5 mL cartridge B/total M water water methanol residue [90Y/177Lu] Y/Lu- C-18 20 mL 3 mL 5 mL cartridge B/total [25] DOTA-TATE 0.3 M 0.3 M ethanol residue ascorbic ascorbic acid acid [123/131I]I-MIBG C-18 5 mL 5 mL 10 mL cartridge B/total [26] water water PB-THF residue (3:1)

M = Monograph (pharmacopoeia or manufacturer)

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1.7 [99mTc]Exametazime extraction method

1. Prepare a 10 mL test tube containing 3 mL of ethyl acetate and 3 mL of saline 2. Add several drops of [99mTc]exametazime (immediately after reconstitution) 3. Cap the tube and mix on a vortex mixer for 1 min 4. Let the tube stand for 1 min to allow the two phases to separate 5. Remove the top layer using a pipette into another test tube 6. Measure the activities in each layer in an ionization chamber 7. Calculate the % lipophilic complex as follows: % primary complex = activity in ethyl acetate layer x 100 total activity in both layers 8. Minimum acceptable value: 80%

Reference: Ballinger JR, Reid RH, Gulenchyn KY. Radiochemical purity of [99mTc]HM-PAO. J Nucl Med 1988; 29: 572-573.

1.8 Radio-High-pressure liquid chromatography (radio-HPLC)

1.8.1 General procedure

RCP testing of SPECT and PET radiopharmaceuticals can be carried out using high-pressure liquid chromatography (HPLC) on systems equipped with a radio-detector and UV detector, though there are exceptions such as 18F- (FDG) where UV detection is not possible and a pulsed amperometric detector is used.

One of the limitations of HPLC is that only compounds which elute from the column are measured and can be quantified. Measurement of recovery of injected activity should be performed for all new compounds and on an occasional basis to check that negligible quantities are being lost, for example due to retention on the guard column. For example, for many F-18 based PET radiopharmaceuticals HPLC conditions are optimised to distinguish the desired radiochemical product and radiolabelled impurities, with free 18F- fluoride content being determined via radio-TLC.

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1.8.2 radio-HPLC systems for SPECT radiopharmaceuticals

Isocratic Radiopharma- Column or Solvent(s) Reference ceutical gradient [99mTc]sestamibi C-8 gradient A: 50 mM ammonium [27] sulphate B: methanol 0%B to 95%B over 5 minutes C-18 isocratic A: methanol [28] B: 50 mM ammonium sulphate C: acetonitrile A:B:C 45:35:20 [99mTc]tetrofosmin PRP-1 gradient A: 10 mM phosphate buffer [29] pH 7.5 B: tetrahydrofuran 0%B to 100%B over 17 minutes PRP-1 isocratic A: acetonitrile [30] B: 10 mM ammonium carbonate A:B 70:30

PRP-1 isocratic A: 5 mM monopotassium [31] phosphate B: acetonitrile A:B 50:50

[99mTc]Tc-MAG3 C-18 isocratic A: ethanol [32] with wash B: 10 mM phosphate buffer pH 6 A:B 5:95 after peak, wash with methanol-water 90:10 C-18 gradient A: 10 mM potassium [33] phosphate with 1% triethylamine pH 5 B: tetrahydrofuran 0%B to 8%B over 30 minutes [99mTc]exametazime PRP-1 gradient A: 20 mM phosphate buffer [9] pH 7.4 B: tetrahydrofuran 0%B to 25%B over 6 minutes PRP-1 gradient A: 10 mM potassium [34] phosphate pH 7 or water containing 1% methanol B: acetonitrile 0%B to 50%B over 5 minutes PRP-1 gradient A: 50 mM sodium acetate [35] pH 5.6 B: tetrahydrofuran 0%B to 100%B over 17 minutes

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[123/131I]I-MIBG C-18 isocratic A: 100 mM sodium [11] phosphate B: tetrahydrofuran A:B 88:12 [123I]ioflupane C-18 isocratic A: methanol [36] B water C: triethylamine A:B:C 85:15:0.2 [123I]iomazenil C-18 isocratic A: methanol [37] B: water A:B 55:45 [111In]In-octreotide C-18 gradient A: saline [38] B: methanol 40%B to 80%B in 20 minutes [111In/90Y/177Lu/ C-18 gradient A: 0.1% TFA in water [39] 68Ga]In/Y/Lu/Ga- B: 0.1% TFA in acetonitrile DOTA-TATE 0-2 min 100%A, 2-20 min 100%A to 100%B 2-[18F]-FDG amino isocratic A: acetonitrile [40] B: water A:B 95:5

1.8.3 radio-HPLC systems for PET radiopharmaceuticals

Isocratic Radiopharma- Column or Solvent(s) Reference ceutical gradient Anion Isocratic 0.1 M aqueous NaOH exchange EP monograph 2-[18F]-FDG Acetonitrile / water 1325 Amino Isocratic (70/30) Anion EP monograph [18F]NaF Isocratic 0.1 M aqueous NaOH exchange 2100 Anion EP monograph [11C]Acetate Isocratic 0.1 M aqueous NaOH exchange 1920 10mM aqueous EP monograph [11C] C-18 Isocratic sodium phosphate 1617 Acetonitrile / water EP monograph [18F]FLT C-18 Gradient (10/90) 2460 Acetonitrile / water EP monograph [18F]FMISO C-18 Gradient (10/90) 2459

1.9 Tips for performing radiochemical chemical purity tests

1.9.1 Thin-layer chromatography:

Equipment

• Always wear gloves when handling chromatography paper • Check whether paper needs to be heat activated prior to use and allow to cool before use if heated beforehand

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• Rinse tanks with the solvent to be used to remove any potential residue from last cleaning/use and then discard • Ensure solvent used is of sufficient depth within the tank (usually about 1 cm) unless sample spot application is a lower point than this • Seal tanks and allow vapour to equilibrate for up to 10 minutes, do not allow solvent to remain within tank for long periods of time prior to use e.g. no more than 40 minutes

Sample preparation

• Do not delay starting testing after sample has been taken • Invert syringe or vial prior to use • Prepare a small hanging droplet in the syringe guard immediately prior to applying the sample to the chromatography paper. • Apply sample to the paper (smallest spot size possible unless the SmPc states different e.g. tetrofosmin) and then place immediately into the tank (if the SmPc does not state that the sample spot must be dry prior to placement in the solvent) • If the sample size is too big then insufficient separation (e.g. streaking) may occur • Try not to spot too many strips of paper in one go to prevent the delay of placement within the tank • For sample spots that do not require drying, this spotting and placement within the tank must be completed as soon as possible to prevent interaction with air and prevent oxidation of the reduced Tc-99m. Kits such as MDP and DPD are particularly sensitive to this • For sample spots that require drying time there is no rush to place the paper within the tank, some kits such as HIDA require longer drying times than others

Tank Placement /Running

• Ensure the paper within the tank is secure e.g. with tape to prevent the paper from sinking into the solvent • Ensure the solvent depth is not above the sample application point • Ensure the paper does not stick to the side of the tank • Do not open and close the tank during running, one the strip is within the tank ensure the lid remains sealed until the solvent front is met • Do not use ink markers to denote the movement of the solvent or solvent front, a pencil is recommended if needed • Remove strips once solvent front is reached and allow to dry by hanging

1.9.2 Cartridge/membrane filtration: • Ensure cartridge/membrane is in the correct orientation prior to use

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• Draw up solvent(s) immediately prior to use, do not allow to sit within syringe for long periods of time e.g. prevent leaching

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References

1. Robbins P. Chromatography of technetium-99m radiopharmaceuticals - a practical guide. New York: Society of Nuclear Medicine; 1984.

2. Zimmer AM, Pavel DG. Rapid miniaturized chromatographic quality-control procedures for Tc-99m radiopharmaceuticals. J Nucl Med. 1977;18:1230–3.

3. Phan T, Wasnich R. Practical nuclear pharmacy. 2nd ed. Honolulu: Banyan Enterprises; 1981.

4. Zimmer AM, Majewski W, Spies SM. Rapid miniaturized chromatography for Tc-99m IDA agents: comparison with gel chromatography. Eur J Nucl Med. 1982;7:88–91.

5. Ohta H, Yamamoto K, Endo K, Mori T, Hamanaka D, Shimazu A, et al. A new imaging agent for medullary carcinoma of the thyroid. J Nucl Med. 1984;25:323–5.

6. Higley B, Smith FW, Smith T, Gemmell HG, Das Gupta P, Gvozdanovic DV, et al. Technetium-99m-1,2-bis[bis(2-ethoxyethyl) phosphino]ethane: human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent. J Nucl Med. 1993;34:30–8.

7. Chen F, Decristoforo C, Rohrbacher B, Riccabona G. A simple two-strip method to determine the radiochemical purity of technetium-99m mercaptoacetyltriglycine. Eur J Nucl Med. 1993;20:334–8.

8. Hung J, Wilson M, Brown M. Rapid preparation and quality control of technetium-99m MAG3. J Nucl Med Technol. 1991;19:176–9.

9. Neirinckx RD, Canning LR, Piper IM, Nowotnik DP, Pickett RD, Holmes RA, et al. Technetium-99m d,l-HM-PAO: a new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion. J Nucl Med. 1987;28:191–202.

10. Thrall JH, Freitas JE, Swanson D, Rogers WL, Clare JM, Brown ML, et al. Clinical comparison of cardiac blood pool visualization with technetium-99m red blood cells labeled in vivo and with technetium-99m human serum albumin. J Nucl Med. 1978;19:796–803.

11. Wieland DM, Wu J, Brown LE, Mangner TJ, Swanson DP, Beierwaltes WH. Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine. J Nucl Med. 1980;21:349–53.

12. Saha G. Fundamentals of nuclear pharmacy. 5th ed. New York: Springer; 2004.

13. Decristoforo C, Knopp R, von Guggenberg E, Rupprich M, Dreger T, Hess A, et al. A fully automated synthesis for the preparation of 68Ga-labelled peptides. Nucl Med Commun. 2007;28:870–5.

14. Yu S. Review of 18F-FDG synthesis and quality control. Biomed Imaging Interv J. 2006;2:e57.

15. Pascali G, D’Antonio L, Bovone P, Gerundini P, August T. Optimization of automated large-scale production of [18F]fluoroethylcholine for PET prostate cancer imaging. Nucl Med Biol. 2009;36:569–74.

16. Rankin A, Zimmer M, Riehle L, Spies S. Rapid miniaturized chromatography system for I-123 ioflupane. J Nucl Med. 2012;53:A3739.

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17. Beer HF, Blauenstein PA, Hasler PH, Delaloye B, Riccabona G, Bangerl I, et al. In vitro and in vivo evaluation of -123-Ro 16-0154: a new imaging agent for SPECT investigations of receptors. J Nucl Med. 1990;31:1007–14.

18. Counsell RE, Ranade VV, Blair RJ, Beierwaltes WH, Weinhold PA. Tumor localizing agents. IX. Radioiodinated . Steroids. 1970;16:317–28.

19. Hammes R, Kies S, Koblenski D, Julin C. A better method for quality control of technetium-99m sestamibi. J Nucl Med Technol. 1991;19:232–5.

20. Hirsch J, Watson M. Rapid quality control of technetium-99m-2-methoxy isobutyl isonitrile (technetium-99m-sestamibi). J Nucl Med Technol. 1996;24:114–8.

21. Ramirez A, Arroyo T, Diaz-Alarcon JP, Garcia-Mendoza A, Muros MA, Martinez del Valle MD, et al. An alternative to the reference method for testing the radiochemical purity of 99Tcm-tetrofosmin. Nucl Med Commun. 2000;21:199–203.

22. Hammes R, Joas LA, Kirschling TE, Ledford JR, Knox TL, Nybo MR, et al. A better method of quality control for 99mTc-tetrofosmin. J Nucl Med Technol. 2004;32:72–8.

23. Mah G, Reilly RM, Wong GL, Houle S. A comparison of three methods to determine the radiochemical purity of 99Tcm-hexamethylpropylene amine oxime (99Tcm- HMPAO). Nucl Med Commun. 1989;10:733–40.

24. Billinghurst MW, Eckert K, Mang’era K. Alternative quality control for technetium-99m IDA complexes. Appl Radiat Isot. 2004;61:1151–5.

25. Pawlak D, Mikołajczak R. Preparation of therapeutic doses of Lu-177 or Y-90 DOTATATE for receptor mediated radiotherapy. Q J Nucl Med Mol Imaging. 2007;51:377.

26. Hung J, Wilson M. Rapid radiochemical purity testing for [131I]m-iodobenzylguanidine. Nucl Med Biol. 1995;22:227–9.

27. Carvalho PA, Chiu ML, Kronauge JF, Kawamura M, Jones AG, Holman BL, et al. Subcellular distribution and analysis of technetium-99m-MIBI in isolated perfused rat hearts. J Nucl Med. 1992;33:1516–22.

28. Hung JC, Wilson ME, Brown ML, Gibbons RJ. Rapid preparation and quality control method for technetium-99m-2-methoxy isobutyl isonitrile (technetium-99m-sestamibi). J Nucl Med. 1991;32:2162–8.

29. Kelly JD, Forster AM, Higley B, Archer CM, Booker FS, Canning LR, et al. Technetium-99m-tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging. J Nucl Med. 1993;34:222–7.

30. Graham D, Millar AM. Artefacts in the thin-layer chromatographic analysis of 99Tcm- tetrofosmin injections. Nucl Med Commun. 1999;20:439–44.

31. Cagnolini A, Whitener D, Jurisson S. Comparison of the kit performance of three 99mTc myocardial perfusion agents. Nucl Med Biol. 1998;25:435–9.

32. Millar AM, Wilkinson AG, McAteer E, Best JJ. 99Tcm-MAG3: in vitro stability and in vivo behaviour at different times after preparation. Nucl Med Commun. 1990;11:405– 12.

33. Shattuck LA, Eshima D, Taylor ATJ, Anderson TL, Graham DL, Latino FA, et al. Evaluation of the hepatobiliary excretion of technetium-99m-MAG3 and reconstitution factors affecting radiochemical purity. J Nucl Med. 1994;35:349–55.

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34. Hung JC, Corlija M, Volkert WA, Holmes RA. Kinetic analysis of technetium-99m d,1- HM-PAO decomposition in aqueous media. J Nucl Med. 1988;29:1568–76.

35. Weisner PS, Bower GR, Dollimore LA, Forster AM, Higley B, Storey AE. A method for stabilising technetium-99m exametazime prepared from a commercial kit. Eur J Nucl Med. 1993;20:661–6.

36. Baldwin RM, Zea-Ponce Y, al-Tikriti MS, Zoghbi SS, Seibyl JP, Charney DS, et al. Regional brain uptake and pharmacokinetics of [123I]N-omega-fluoroalkyl-2 beta- carboxy-3 beta-(4-iodophenyl)nortropane esters in baboons. Nucl Med Biol. 1995;22:211–9.

37. Zoghbi SS, Baldwin RM, Seibyl JP, al-Tikriti MS, Zea-Ponce Y, Laruelle M, et al. Pharmacokinetics of the SPECT benzodiazepine receptor radioligand [123I]iomazenil in human and non-human primates. Int J Rad Appl Instrum B. 1992;19:881–8.

38. Krenning EP, Bakker WH, Kooij PP, Breeman WA, Oei HY, de Jong M, et al. Somatostatin receptor with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide. J Nucl Med. 1992;33:652–8.

39. Wehrmann C, Senftleben S, Zachert C, Muller D, Baum RP. Results of individual patient dosimetry in peptide receptor therapy with 177Lu DOTA-TATE and 177Lu DOTA-NOC. Cancer Biother Radiopharm. 2007;22:406–16.

40. Hamacher K, Coenen HH, Stocklin G. Efficient stereospecific synthesis of no-carrier- added 2-[18F]-fluoro-2-deoxy-D- using aminopolyether supported nucleophilic substitution. J Nucl Med. 1986;27:235–8.

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