[18F]ZDG2 First-in-Human PET Imaging in PAH

Healthy Volunteer Criteria

Inclusion Criteria- Healthy Volunteers

1. Age 21-75 years (inclusive) at time of consent

2. Body Mass Index 18.5-35 kg/m²

3. Willing and able to provide written informed consent

4. Willing and able to comply with all study procedures

5. Able to lie flat in supine position for 60 minutes without significant discomfort

6. No history of cardiovascular disease including:

   • Symptomatic Coronary artery disease
   • Significant Valvular heart disease (stenotic or regurgative disease of moderate or grater severity)
   • Congenital heart disease
   • Symptomatic Arrhythmias
   • Pulmonary hypertension
   • Thromboembolic disease (history of recurrent pulmonary embolisms)

7. Normal baseline electrocardiogram within 28 days

8. Normal baseline echocardiogram within 6 months demonstrating:

   • Normal RV size and systolic function (Tricuspid Annular Plane Systolic Excursion>17 mm)
   • No tricuspid regurgitation jet or estimated Right Ventricular Systolic Pressure <35 mmHg
   • Normal Left Ventricle size and systolic function (Left Ventricular Ejection Fraction ≥50%)
   • No significant valvular disease

9. Baseline NT-proBNP <125 pg/mL (or BNP <50 pg/mL)

10. Non-smoker OR former smoker with quit date ≥1 year ago and <10 pack-year history

11. For women of childbearing potential:

    -Agrees to use highly effective contraception from screening through 30 days after imaging

12. For men with Women of Childbearing Potential partners:

    • Agrees to use barrier contraception from screening through 30 days after imaging

Exclusion Criteria- Healthy Volunteers

1. Active cancer (except non-melanoma skin cancer >2 years disease-free), metabolic encephalopathy, infection, or cardiovascular disease.

2. Active hematological, renal, pulmonary, endocrine, or hepatic disorders, except for treated thyroid disease.

3. History of pulmonary disease including:

   • Asthma
   • Chronic Obstructive Pulmonary Disease
   • Interstitial lung disease
   • Prior pneumonia with residual changes
   • Sleep apnea

4. Participation in any investigational diagnostic or therapeutic radiopharmaceutical studies in the last year.

5. Coronary revascularization (Percutaneous Coronary Intervention or Coronary Artery Bypass Graft) within 6 months

6. Stroke or Transient Ischemic Attack within 6 months

7. Uncontrolled systemic hypertension (Systolic Blood Pressure(SBP)>160 or Diastolic Blood Pressure(DBP)>100 mmHg)

8. Resting systolic blood pressure <90 mmHg

9. Clinically significant arrhythmia requiring treatment

10. Use of any prescription medication

11. Significant alcohol use (>14 drinks/week for men, >7 drinks/week for women)

12. Illicit drug use within 2 years (including, use of stimulants such as methamphetamine)

13. Use of amphetamine weight loss drugs

14. Portal hypertension

15. Radiation exposure >50 mSv in the past 12 months

16. Occupational radiation exposure

17. Known genetic risk factors for PAH (ex: Bone Morphogenetic Protein Receptor Type 2 mutations)

18. History of scleroderma

19. History of pre-term birth

20. History of Human Immunodeficiency Virus

21. Known allergy or hypersensitivity to any component of the investigational product

22. Contraindication to Positron Emission Tomography / Computed Tomography imaging

23. Weight >227 kg (500 lbs. - scanner table limit)

24. Any condition that, in the opinion of the investigator, would compromise subject safety or study data quality

25. Incarceration

PAH Patients Criteria

Inclusion Criteria- PAH Patients

1. Age 21-75 years (inclusive) at time of consent

2. Body Mass Index 18.5-40 kg/m²

3. Willing and able to provide written informed consent

4. Willing and able to comply with all study procedures

5. Able to lie flat (or semi-recumbent with 15-30° elevation) for 60 minutes

6. Confirmed diagnosis of pulmonary arterial hypertension (World Health Organization (WHO) Group 1) by right heart catheterization meeting ALL of the following hemodynamic criteria within the last 3 months:

   • Mean pulmonary artery pressure ≥20 mmHg
   • Pulmonary artery wedge pressure ≤15 mmHg
   • Pulmonary vascular resistance ≥3 Wood Units

7. PAH etiology limited to WHO Group 1 subtypes:

   • Idiopathic PAH

   • Heritable PAH

   • Drug or toxin-induced PAH

   • Associated PAH including:

     • Connective tissue disease: scleroderma, lupus, Mixed Connective Tissue Disease, etc.
     • Congenital heart disease: repaired shunts only
     • Portal hypertension
     • HIV infection

8. WHO Functional Class I, II or III:

   • Class I: No limitation of physical activity
   • Class II: Slight limitation of physical activity; ordinary activity causes symptoms
   • Class III: Marked limitation of physical activity; less than ordinary activity causes symptoms

9. 6-minute walk distance: 150-450 meters (performed with 8 weeks of screening)

   -≥150 meters: Ensures patient can complete study procedures

   -≤450 meters: Ensures meaningful disease severity for signal detection

10. Adequate organ function:

    • Serum creatinine ≤2.0 mg/dL OR estimated Creatinine Clearance ≥30 mL/min
    • AST/ALT ≤2.5× ULN
    • Total bilirubin ≤1.5× ULN

11. Clinically stable for ≥8 weeks prior to enrollment:

    • No hospitalization for PAH or heart failure
    • No PAH exacerbation or clinical worsening
    • No syncope or presyncope
    • No escalation of diuretic dose for >2 weeks

12. Stable PAH-specific medication regimen for ≥8 weeks:

    • No addition, discontinuation, or dose change of:
    • Endothelin receptor antagonists
    • Phosphodiesterase-5 inhibitors
    • Soluble guanylate cyclase stimulators
    • Prostacyclin pathway agents
    • Activin Receptor Antagonist (Sotatercept)

13. Comprehensive echocardiogram within 8 weeks demonstrating:

    • RV size and function quantified (TAPSE, RV S')
    • Estimated RVSP documented, if adequate tricuspid regurgitation jet available
    • No severe LV dysfunction (LVEF ≥40%)
    • No more than moderate valvular disease

14. Pulmonary function tests (as measured per standard of care) within 12 months demonstrating:

    • Forced Expiratory Volume(FEV)1/Forced Vital Capacity (FVC) >0.70 OR if <0.70, FEV1 >60% predicted
    • DLCO >30% predicted

15. High-resolution chest CT (as measured per standard of care) within 12 months demonstrating:

    • No significant parenchymal lung disease (emphysema, fibrosis)
    • Enlarged main pulmonary artery typical of PH (PA diameter >29 mm)
    • No evidence of chronic thromboembolic disease

16. Ventilation-perfusion scan (as measured per standard of care) within 12 months demonstrating:

    • Low probability OR normal study
    • No mismatched perfusion defects (excludes Chronic Thromboembolic Pulmonary Hypertension)

17. For Women Of Childbearing Potential:

    -Agrees to use highly effective contraception through 30 days after imaging

18. For men with Women Of Childbearing Potential partners:

    -Agrees to use barrier contraception through 30 days after imaging

19. Life expectancy ≥6 months in the judgment of the investigator

Exclusion Criteria- PAH Patients

1. Acute coronary syndrome within 6 months

2. Coronary revascularization (PCI or CABG) within 6 months

3. Stroke or TIA within 6 months

4. Uncontrolled systemic hypertension (SBP >160 or DBP >100 mmHg)

5. Resting systolic blood pressure <90 mmHg

6. Clinically significant arrhythmia requiring treatment (except stable atrial fibrillation)

7. Active pulmonary infection or pneumonia within 3 months

8. Pulmonary embolism (acute) within 6 months

9. Classification of other PH groups confirmed by:

   • Group 2 (LHD): PAWP ≤15 mmHg, no significant LV disease on echo
   • Group 3 (lung disease): FEV1/FVC >0.70 OR FEV1 >60% if obstructive; DLCO >40% predicted; no significant interstitial lung disease on CT in the past 12 months (If no PFT available for the past 12 months patient will need one at the time of screening)
   • Group 4 (CTEPH): Ventilation-perfusion scan any time since diagnosis showing low probability or normal (no mismatched defects)
   • Group 5: No evidence of multifactorial/unclear PH mechanisms
   • For PAH: Significant Group 2, 3, 4, or 5 PH contribution

10. WHO Functional Class IV (symptoms at rest - too sick for study)

11. Radiation exposure >50 mSv in the past 12 months

12. Occupational radiation exposure

13. Cirrhosis with portal hypertension

14. Known allergy or hypersensitivity to any component of the investigational product

15. Contraindication to PET/CT imaging

16. Weight >227 kg (500 lbs. - scanner table limit)

17. Active malignancy (except non-melanoma skin cancer >2 years disease-free)

18. Participation in any investigational diagnostic or therapeutic radiopharmaceutical studies in the last year.

19. Any condition that, in the opinion of the investigator, would compromise subject safety or study data quality

20. Incarceration