Rhenium Radiopharmaceuticals: Products Having Potential to Move from Bench to Bedside-1st World Rhenium Conference 11-13, KMCH, Coimbatore, India

M.R.A. Pillai Ph.D.; D.ScMolecular Group of Companies, Cochin

[email protected]://independent.academia.edu/PillaiMRA

Clinical Utilization of Re-188

Radiopharmaceuticals:Issues and solutions

Slide from Dr. R. Baum

177Lu and 90Y can be mass produced

Lutetium-177◦176Lu(n,g)177Lu

Specific activity >20 Ci/mgYttirum-90◦90Sr/90Y generator◦Large inventory of 90Sr◦Annual Production 600 Mega Curie

Production of long lived parent radionuclides for generators : 68Ge, 82Sr, 90Sr and 188W. (IAEA 2010)

Yttrium-90 Different technologies are available for the separation of 90Y from 90Sr

The electrochemical generator ‘Kamadhenu’ can provide a continuous source of 90Y from a single source of 90Sr

Current Status in India

90Y is not locally available 90Y microspheres for TARE can be imported at a cost of 0.6 million INR equivalent to ~ 10,000 USD

Thus the interest in 188Re as a cost effective alternative despite no local production of 188W or W/Re generator in India

188Re is a very useful till there is wider availability of 90Y.

There are three issues in the wider use of 188Re◦Availability of 188W◦Preparation of column generator◦Radiopharmaceuticals development

1. Production of 188W

Reactor production and processing of 188W. Knapp et al. 2010

Annual Production capacity 500-1000 CiEquivalent to 500-1000 generatorsSpecific activty 4-5 Ci/g

2. Column Generator

Issues with Column Generator Production 188W maximum specific activity is 4-5 Ci/g

Capacity of alumina for 188Re <50 mg/g2 g alumina can take ~ 400-500 mCi of activity

Generator with capacity >500 mCi will result in large elution volume.

Post elution concentration is an option; but a difficult option and not preferred

Nano crystalline Titania : 300 mg/g Nanocrystalline Zirconia : 325 mg/gNanocrystalline Alumina : 500 mg/g

Nano Alumina as column Matrix

1 g of nano-alumina generator can load >2 Ci of 188W

Low elution volume and high concentration eluent

Extended use of generator Nanoalumina based generator are acceptable to regulators

Logistics of Gamma Alumina based Generators

Elution profile of Nano alumina Column generator

Radio-rheniums

185Re(n,g)186Re; s 114 barns187Re(n,g)188Re; s 72 barnsMultivalent and versatile chemistry

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Mixed Radionuclide Therapy

A natural rhenium target when irradiated for 7 days reactor gives a mixture of 186Re and 188Re at ~40:60 ratio:

A day cooling will yield a mixture of 60:40.

Both the radionuclides are useful for therapy

3. Rhenium ChemistryTechnetium and rhenium has identical chemical properties

Hence most technetium complexes can be duplicated with rhenium

The above statements are true to some extent; but miserably fail once we start exploring

the chemistry

Products developed

186/188Re-HEDP186/188Re-CTMP186/188Re-DMSA(Sn)186/188Re-DMSA(MBS)186/188Re-HA particles186/188Re-EC

• Natural rhenium metal irradiated for 7 days; followed by 4 days cooling•Dissolution in HNO3, evaporation and addition of ammonia to convert to ammonium perrhenate, poor complexation •Extraction in MEK and dissolution in saline improves the complexation efficiency

186/188Re-HEDP50 mg HEDP10 mg SnCl2100 mg rhenium carrierPerrhenate (NaReO4)Complexation at pH 2, 100oCStorage upto 4 days at pH 2 and at 4oC

Adjusting the pH to 8 reduces the kidney dose

Bone uptake ~30% at 48 h p.i.

99mTc(V)DMSA for imaging medullary thyroid carcinoma

188Re(V)DMSA for treatment of medullary thyroid carcinoma

High renal uptake Metastatic bone pain palliation

186/188Re-DMSA with different reducing agents: Stannous chloride and Sodium metabisulphite

Locoregional injection retained >98% of the activity in the knee joint

ConclusionsThe limitations w.r.t 188W production and availability will continue

Nano-alumina based column generator will be advantageous

188Re-HEDP could be a readily available radiopharmaceutical for bone pain palliation.

188Re-CTMP might be better than 188Re-HEDP; and worth exploring

188Re-DMSA is useful for medullary thyroid carcinoma.

Depending upon the method of production; rhenium complexes could be different and hence need careful evaluation

Thank you