A Study of Healthy Subjects to Assess the Effect of LY450139 on Amyloid Beta Peptide Production Rate and or Dose Response.

• To test the hypothesis that LY450139 has an effect on fractional clearance rate of Amyloid Beta assayed from CSF samples in LY450139-treated subjects compared to placebo-treated subjects. [ Time Frame: 0-36 hours post dose ] [ Designated as safety issue: No ]
• To study and evaluate other biomarkers, such as sAPPB and sAPPA that may enable drug effectiveness to be predicted. [ Time Frame: 0-36 hours post dose ] [ Designated as safety issue: No ]
• To measure concentrations of Amyloid Beta(1-40), Amyloid Beta(1-42), and leucine in CSF by mass spectrometry. [ Time Frame: 0-36 hours post dose ] [ Designated as safety issue: No ]
• To explore the relationship between Amyloid Beta plasma decrease and Amyloid Beta synthesis rate as determined by CSF measurements. [ Time Frame: 0-36 hours post dose ] [ Designated as safety issue: No ]

To test that LY450139, a gamma-secretase inhibitor, will reduce the rate of newly synthesize Amyloid Beta by determining the amount of newly synthesized 13C6 leucine-labeled Amyloid Beta in lumbar cerebrospinal fluid from LY450139 treated subjects compared with placebo treated subjects.

• Drug: LY450139
• Drug: placebo

• Experimental: 1
  100 mg LY 450139 oral
  Intervention: Drug: LY450139
• Experimental: 2
  140 mg LY450139 oral
  Intervention: Drug: LY450139
• Experimental: 3
  280 mg LY450139 oral
  Intervention: Drug: LY450139
• Experimental: 4
  Placebo
  Intervention: Drug: placebo

Inclusion Criteria:

• Healthy volunteers: Men within the ages of 21 and 50

Exclusion Criteria:

• Have serious or unstable medical conditions
• Have a history of serious infections affecting the brain or head trauma resulting in protracted loss of consciousness within the last 5 years or multiple episodes of head trauma
• Have a history of primary or recurrent malignant disease
• Have a recent laboratory result indicating a clinically significant laboratory abnormality as determined by the investigator
• Have a history of chronic alcohol or drug abuse within the past 5 years
• Have a known history of Human immunodeficiency virus (HIV), afebrile seizures, or clinically significant multiple drug allergies
• Are judged clinically by the investigator to be at serious risk for suicide
• Have electrocardiogram abnormalities obtained at visit 1 that in the opinion of the investigator are clinically significant
• Use of prescription or over the counter medications that cannot safely be discontinued within 14 days prior to visit 2
• Have criteria that would preclude a LP such as allergy to all local anesthetics; have a local infection at the site of the LP or have any medical condition requiring treatment with warfarin or heparin.
• Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
• Are investigator site personnel directly affiliated with this study and or immediate families.
• Are Lilly employees