Synthesis of 18Ffluoroalkyl esters of carfentanil

1
Synthesis of 18Ffluoroalkyl esters of
carfentanil

• 11CCarfentanil has several difficulties
• Short half-life (20 min)
• Extremely potent! (pharmacological effect at 2
  ?g/70kg patient)
• High specific activity required
• 740MBq (20mCi) administration ? 88.8TBq/mmol
  (2.40Ci/?mol)
• Possible, but takes great care to achieve
• A solid quality control method is required!

G. Henriksen et al, J Label Compd Radiopharm
2005, 48, 771-779.
2
Research Objectives

• To synthesize two 18F-fluoroalkyl cafentanil
  derivatives
• To stabilize the ester bond
• To lower the toxicity profile
• To improve the signal intensity of cafentanil PET
  studies

3
Fluoroalkyl Precursors

• Prepared by standard reactions
• Direct route to 1-2 fluoroiodoethane low yield
• Tosyl and iodo fluoroethanes reacted with
  carfentanyl carboxylate

4
Fluoroethyl Carfentanil Optimization

• DMF, 150oC, 20mM NaI, 15.9mM TBAF
• Optimized
• 368
• gt97 RC purity
• SA gt 35TBq/mmol

5
Fluoropropyl Carfentanil Optimization

• DMF, 160oC, 15.9mM TBAF
• Optimized
• 62
• gt97 RC purity
• SA gt 27TBq/mmol

6
Are these Useful Imaging Compounds?

• Unanswered questions in this paper
• Does the agent provide a useful image?
• Is it stable enough in vivo to bind to the
  receptor before degradation of the ester bond?
• Does it accumulate in other organs to an extent
  that the image quality is degraded or that
  radiation dose accumulation becomes a problem?

Henrikson et al, Eur. J. Nuc. Med., 2004, S02,
S250. Henrikson et al, Biorg Med Chem Letters,
2005, 15, 1773-1777. Henrikson et al, Drug
Development Research, 2006, 67, 890-904.
7
Surprise!

• Published before paper!
• Good uptake 3.5-5.5 ID/g
• Cerebral clearance too fast
• Ester bond broken by esterases in the brain?